Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature

  • Karim Elhennawy1,
  • Seif Reda1,
  • Christian Finke1,
  • Luitgard Graul-Neumann2, 3,
  • Paul-Georg Jost-Brinkmann1 and
  • Theodosia Bartzela1Email author
Journal of Medical Case Reports201711:233

https://doi.org/10.1186/s13256-017-1387-z

Received: 1 March 2017

Accepted: 11 July 2017

Published: 15 August 2017

Abstract

Background

Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient’s family was included in Chen and colleagues’ study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature.

Case presentation

We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis.

Conclusions

The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.

Keywords

Case report Dental PRDM12 gene Hereditary sensory and autonomic neuropathy HSAN-VIII Oral manifestations

Background

Hereditary sensory and autonomic neuropathy (HSAN) comprises a group of genetic disorders involving sensory and autonomic dysfunctions [1]. HSAN was classified into five main types [2]. Later, it was modified into subtypes [35] according to gene mutations, mode of inheritance, and clinical characteristics. HSAN types VI and VII were mentioned in the classification of Haga et al. [5]: Online Mendelian Inheritance in Man (OMIM) 614653 and 615548 respectively. HSAN type VIII (OMIM 616488) was recently characterized by Chen et al. [6] as a rare autosomal recessive disorder. Our patient’s family was included in their study. General characteristics, mode of inheritance, onset, and genes involved in each type of HSAN are presented in Table 1.
Table 1

Classification of recent types and subtypes of hereditary sensory (and autonomic) neuropathy

Types of HSAN

OMIM

Inheri.

Onset

Clinical characteristics

Somatosensory modalities

Sweating

Genes/ locus

HSAN-IA [2, 25, 28, 33, 34]

162400

AD

Mostly adolescence to adulthood

Hearing loss, loss of distal reflexes/distal muscle weakness, (no autonomic dysfunction)

Loss of pain and temperature sensation, lancinating pain

Normal

SPTLC1/9q22.31

HSAN-IB [2, 25, 28, 3335]

608088

AD

Adulthood

Chronic cough, gastropharyngeal reflux, hearing loss, alacrima, impotence

Sensory loss, lancinating pain

Normal to mild distal hypohidrosis

SPTLC1/3p24-p22

HSAN-IC [2, 25, 28, 33, 34, 36]

613640

AD

Mostly adulthood

Ulcerative mutilations, variable distal motor involvement, distal muscle weakness, osteomyelitis

Loss of pain, lancinating pain, loss of temperature sensation in parts of the body, sensory loss in the upper and lower limbs

Normal

SPTLC2/14q24.3

HSN-ID [2, 25, 28, 33, 34, 37]

613708

AD

Adulthood

Ulcerative mutilations, trophic skin and nail changes, distal amyotrophy in the lower limbs

Distal sensory loss of the lower limbs

Normal

ATL1/14q22.1

HSN-IE [2, 25, 28, 33, 34, 38]

614116

AD

Adulthood

Ulcerative mutilations, hearing loss, dementia

Loss of all somatosensory modalities, lancinating pain

Normal

DNMT1/19p13.2

HSN-IF [2, 25, 28, 33, 34, 39]

615632

AD

Adulthood

No autonomic involvement, diminished tendon reflexes, painless ulceration of the feet

Distal sensory loss of the lower limbs

Normal

ATL3/11q13.1

HSAN-IIA [2, 25, 28, 33, 34, 40]

201300

AR

Childhood

Self-mutilation behavior resulting in extensive orofacial injuries, weakness, acropathy

Loss of pain, temperature and touch sensation, no autonomic dysfunction

Normal

WNK1/12p13.33

HSAN-IIB [2, 25, 28, 33, 34, 41]

613114

AR

Childhood

Ulcerative mutilation of hands, feet, and orofacial structures, osteomyelitis, urge incontinence

Impaired nociception

Hyperhidrosis

FAM134B/5p15.1

HSN-IIC [2, 25, 28, 33, 34, 42]

614213

AR

Childhood to adolescence

Ulcerative mutilation and orofacial injuries, absent deep tendon reflexes, minor distal weakness, distal numbness of the hands and feet

Impaired position vibration senses

N/A

KIF1A/2937.3

HSAN-IID [2, 4, 25, 28, 33, 34, 43]

243000

AR

Congenital or adolescence

Autonomic nervous dysfunction, hearing loss, hyposmia, bone dysplasia, orofacial self-mutilation injuries

Loss of pain and temperature sensation, hypogeusia

Hypohidrosis

SCN9A/2q24.3

HSAN-III [2, 26, 29, 33, 34, 44, 58 63–66]

223900

AR

Congenital

Profound autonomic dysfunction, vasomotor instability, absence of deep tendon reflexes, alacrima, impaired blood pressure regulation, failure to thrive, orofacial self-mutilation, absent fungiform papillae on the tongue, increased salivation, low caries index

Loss of pain and temperature sensation

Hyperhidrosis

IKBKAP/9q31.3

HSAN-IV [2, 8, 9, 11, 13, 14, 26, 28, 29, 34, 35, 4451]

256800

AR

Congenital

Self-mutilation with orofacial injuries, deep tendon reflexes usually intact, recurrent fever, corneal lesions, mental retardation, recurrent infections, skin hyperkeratosis and fissuring, generalized tonic-clonic seizures

Loss of pain and temperature sensation

Hypohidrosis to anhidrosis

NTRK1/1q23.1

HSAN-V [2, 26, 29, 34, 35, 52]

608654

AR

Congenital

Similar to HSAN IV

Loss of pain and reduced thermal sensation, loss of deep pain perception

Normal to hypohidrosis

NGFB/1p13.2

HSAN-VI [33, 53]

614653

AR

Congenital

Lack of psychomotor development, autonomic abnormalities, absence of deep tendon reflexes, feeding and respiratory difficulties, neonatal hypotonia, alacrima, blotching

Loss of pain and temperature sensation

N/A

DST/6p12.1

HSAN-VII [33, 54, 55]

615548

AD

Congenital

Self-mutilation, painless fractures, delayed motor development, gastrointestinal dysfunction

Loss of pain sensation

Hyperhidrosis

SCN11A/3p22.2

HSAN-VIII [6, 30]

616488

AR

Onset in infancy

Self-mutilation behavior with orofacial injuries, painless fractures, skin and bone infections, corneal injuries, no mental retardation

Reduced pain and temperature sensation

Hypohidrosis

PRDM12/9q34.12

HSN with spastic paraplegia [33, 34]

256840

AR

Early childhood

Mutilation acropathy, septic paraplegia

Loss of all somatosensory modalities

Normal

CCT5/5p15.2

AD autosomal dominant, AR autosomal recessive, ATL1 atlastin GTPase 1, ATL3 atlastin GTPase 3, CCT5 chaperonin TCP1 subunit 5, DNMT1 DNA (cytosine-5-)-methyltransferase 1, DST dystonin, FAM134B family with sequence similarity 134 member B, HSAN hereditary sensory and autonomic neuropathy, HSN hereditary sensory neuropathy, IKBKAP inhibitor of kappa light polypeptide gene enhancer in B-cells kinase complex-associated protein, Inheri. mode of inheritance, KIF1A kinesin family member 1A, N/A not available, NGFB nerve growth factor (beta polypeptide), NTRK1 neurotrophic tyrosine kinase-1 receptor, OMIM Online Mendelian Inheritance in Man, PRDM12 PR domain-containing protein 12, SCN9A sodium channel, voltage gated type IX alpha subunit, SCN11A sodium channel, voltage gated, type XI alpha subunit, SPTLC1, serine palmitoyltransferase long chain base subunit 1, SPTLC2, serine palmitoyltransferase long chain base subunit 2, WNK1 WNK lysine deficient protein kinase 1

HSAN-VIII is characterized by five main features: insensitivity to pain and thermal stimuli, self-mutilation behavior, altered sweat and tear formation, absence of corneal reflexes, and presence of repeated infections of the skin and bone [6]. The syndrome was confirmed in 21 patients [6] and 10 different homozygous mutations in the PR domain-containing protein 12 gene (PRDM12) were identified [6]. Mutations in the PRDM12 gene in humans cause developmental defects in the sensory neurons, leading to loss of pain perception. Great loss of the small myelinated Aδ fibers occurred in patients with HSAN-VIII. Skin biopsies revealed that the peripheral terminals of unmyelinated C fibers were altered [6].

Patients carrying PRDM12 mutations lack the sensation of acute pain and temperature. Thus, these patients have numerous injuries, which may lead to recurrent infections of skin and bones, and bone deformities later in life. In addition, they lack corneal reflexes, which leads to progressive corneal scarring. However, other senses like light touch, vibration, and proprioception are normal. The only autonomic dysfunction observed was the reduction in sweating and tears formation. Intellectual abilities in patients with HSAN-VIII are normal [6].

Insensitivity to pain leads to severe oral mutilations, such as tooth luxation, severe dental attrition, premature tooth loss, bite wounds, and ulcerations [79]. The tongue, followed by the lips, and the oral mucosa, are the most common sites of self-inflicted injuries [10, 11]. The diagnosis of HSAN is challenging due to its rarity, similarity in clinical presentation to other auto-aggression or self-mutilation diseases, and lack of simple diagnostic tests [12]. It is mainly confirmed by the clinical presentation, genetic analysis, pharmacological tests, and neuropathological examinations [13]. Management of patients affected by HSAN-VIII is complicated due to the patients’ lack of awareness and perception of pain.

We aimed to present the manifestations and dental management of a patient with HSAN-VIII harboring the homozygous mutation c.516G>C (p. Glu172Asp) in the PRDM12 gene [6], who has been followed up in our clinic for 16 years. A review on PubMed library (January 1985 to December 2016) on patients with HSAN with oral manifestations was performed (Table 2).
Table 2

Literature review concerning oral manifestations associated with hereditary sensory (and autonomic) neuropathy

Year of pub.

Authors

Type

Gene

Country/ ethnic group

Ts

N

Age

G

General characteristics

Oral manifestations

2016

Eregowda et al. [56]

IV

NTRK1

India/ Indian

CR

1

11 y

F

Thermal insensitivity, anhidrosis, low intelligence, deformed interphalangeal joints of fingers, corneal scarring, skin infections, osteomyelitis

Oral self-mutilation, dental traumata

2015

Ravichandra et al. [13]

IV

NTRK1

India/

N/A

CR

1

7 y

F

Insensitivity to pain and temperature, anhidrosis, self-mutilation, preservation of other sensory modalities, recurrent fever

Orofacial self-mutilation, dental traumata

2015

Ashwin et al. [11]

IV

NTRK1

India/

N/A

CS

8

4–17 y

6 M

2 F

Insensitivity to pain, self-mutilation, recurrent fever, recurrent infection in the lower limbs

Oral self-mutilation

2015

Chen et al. [6]

VIII

PRDM12

Inter/

Inter

GA

21

3–40 y

13 M

8 F

Insensitivity to pain and temperature, hypohidrosis, self-mutilation behavior, skin and bone infections, painless fractures, corneal injuries, no mental retardation

Orofacial self-mutilation

2014

Özkaya et al. [57]

IV

NTRK1

Turkey/

N/A

CR

1

10 y

M

Recurrent fever, anhidrosis, ulcers on the skin, osteomyelitis, hyperkeratotic lesions on elbows and knees

Orofacial self-mutilation

2014

Guven et al. [44]

IV

NTRK1

Turkey/

Turkish descent

CS

2

1 y, 17 y

M

Insensitivity to pain and temperature, self-mutilation behavior, non-healing skin, ulcerations on the dorsum of the hands, anhidrosis, hypo- and hyper-pigmented skin

Orofacial self-mutilation

2013

Gao et al. [8]

IV

NTRK1

China/

N/A

CR

1

8 m

M

Recurrent fevers, anhidrosis,

dry warm skin, congenital corneitis

Oral self-mutilation, dental caries, malocclusion, cleft palate

2013

Fruchtman et al. [58]

IV

N/A

Israel/

N/A

CS

30

1 m–15 y

16 M

14 F

Infections, fever, orthopedic lesions

Orofacial self-mutilation

2010

Hutton and McKaig [45]

V

N/A

UK/

N/A

CR

1

6 y

F

N/A

Orofacial self-mutilation

2010

Zilberman et al. [46]

III

N/A

Israel/

N/A

HA

17

N/A

N/A

N/A

Thicker enamel formation

2009

Neves et al. [9]

IV

NTRK1

Brazil/

N/A

CR

1

2 y

F

Unexplained fever episodes, anhidrosis, self-mutilation behavior, mental retardation

Oral self-mutilation

2009

Paduano et al. [59]

IV

N/A

Italy/

Italian descent

CR

1

8.11 y

M

Self-mutilation, recurrent fever, osteomyelitis

Oral ulcers, limited mouth opening

2008

Romero et al. [60]

IV

N/A

Spain/

N/A

CR

1

22 m

F

Self-mutilation, recurrent fever

Orofacial self-mutilation

2008

Singla et al. [47]

V

N/A

India/

Indian descent

CR

1

10 y

M

Insensitivity to pain, normal response to thermal stimuli, bilateral corneal opacities, hypoplasia of the nipples

Presence of severe maxillary ridge resorption, congenitally missing permanent teeth

2006

Butler et al. [25]

IV

NTRK1

Ireland/

N/A

CR

1

9 m

M

Self-mutilation injuries on wrist and feet, insensitivity to pain, normal reaction to thermal stimuli

Orofacial self-mutilation

2006

Schalka et al. [27]

IV

N/A

Brazil/

Caucasian

CR

1

16 m

F

Lack of painful stimuli, episodes of unexplained fever, hypohidrosis

Orofacial self-mutilation

2006

Siqueira et al. [48]

V

N/A

Brazil/

N/A

CS

2

22 y, 16 y

1 M

1 F

Insensitivity to pain, self-mutilation behavior

Orofacial self-mutilation

2003

Bonkowsky et al. [12]

IV

NTRK1

USA/

Northern European

CR

1

4 m

M

Hyperkeratosis on palms, skin fissuring

Orofacial self-mutilation

2002

Mass et al. [52]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

28

N/A

N/A

N/A

Low levels of mutans streptococci and lactobacilli in saliva, high salivary flow

2002

Wolf et al. [61]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

46

6–16 y

31 M

15 F

Impaired pain perception, skeletal deformities, small stature, failure to thrive, recurrent pneumonia, orthostatic hypotension

Progressive degeneration of tongue fungiform papillae and taste buds, impaired taste, excessive drooling, impaired swallowing

2000

Theodorou et al. [62]

IV

N/A

Greece/

N/A

CR

1

4 y

M

Insensitivity to pain, self-mutilation, bone fractures, anhidrosis, mental retardation

Orofacial self-mutilation

2000

Erdem et al. [49]

IV

N/A

Turkey/

N/A

CR

1

10 y

M

Acute tibia osteomyelitis, broken finger tips

Malformed oral configuration, orofacial self-mutilation

1999

Kim et al. [50]

IV

N/A

Korea/

N/A

CR

1

16 m

M

Self-mutilation, fever, anhidrosis, generalized tonic-clonic seizures

Orofacial self-mutilation

1998

Amano et al. [7]

IV

N/A

Japan/

Asian

CS

18

1–22 y

12 M

6 F

Self-mutilation behavior, insensitivity to pain, anhidrosis, infections, malnutrition

Orofacial mutilation, premature loss of teeth, intraoral scars and ulcers, severe bruxism, dental traumata, halitosis

1998

Rodd et al. [51]

II

N/A

UK/

Asian

CR

1

4 y

M

Sensory loss affecting all modalities of sensation predominantly involving the limbs, mutilation, anhidrosis, acropathy of finger tips and feet

Full-thickness loss of the tongue tip, tissue loss from the lower lip, loss of pain sensation

1998

Mass et al. [63]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

32

5.8–19.8 y

17 M

15 F

Decreased pain sensation, impaired temperature and blood pressure regulation, alacrima, absent tendon reflexes

Orofacial self-mutilation, dental traumata, low caries index, hypersalivation, absence of the fungiform papillae on the tongue

1996

Mass et al. [64]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

20

5–39 y

14 M

6 F

Decreased pain sensation, impaired temperature and blood pressure regulation, alacrima, absent tendon reflexes

Orofacial self-mutilation

1994

Mass and Gadoth [65]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

38

N/A

23 M

15 F

Decreased pain sensation, impaired temperature and blood pressure regulation, alacrima, absent tendon reflexes

Dental traumata

1992

Mass et al. [66]

III

N/A

Israel/ Ashkenazi-Jewish descent

CS

66

N/A

N/A

Decreased pain sensation, impaired temperature, impaired blood pressure regulation, absent tendon reflexes, alacrima

Orofacial self-mutilation, dental traumata, low caries index, hypersalivation, absence of the fungiform papillae on the tongue

1989

Kouvelas and Terzoglou [28]

IV

N/A

Greece/

N/A

CR

1

5.5 y

M

Insensitivity to pain, self-mutilation, fever, anhidrosis

Orofacial mutilation

1987

Brahim et al. [67]

IV

N/A

USA/

N/A

CR

2

11 y,

7 y

M

Self-mutilation, fever, anhidrosis, osteomyelitis

Orofacial mutilation

1986

Thompson et al. [68]

III

N/A

USA/

Caucasian

CR

1

31 y

M

Insensitivity to pain, blotching of skin, diminished lacrimation

Orofacial mutilation (including auto-extraction of teeth), diminished taste sensation

2016

Zhang et al. [30]

VIII

PRDM12

N/A

CS

5

23–57 y

4 M

1 F

Insensitivity to pain, normal neurological examinations and intellect, corneal abrasions, lack of tear production, recurrent infections, unexplained self-mutilation

Unexplained orofacial mutilation

Review articles

2015

Haga et al. [5]

IV, V

NTRK1, NGFB

Japan/

N/A

RA

N/A

N/A

N/A

Repeated fractures, joint dislocations, arthritis, osteomyelitis, avascular necrosis, Charcot arthropathy

Oral self-mutilation (including auto-extraction of teeth)

2014

Kumar et al. [69]

IV

NTRK1

India/

N/A

RA

N/A

N/A

N/A

N/A

Orofacial self-mutilation, premature loss of teeth, osteomyelitis, fractures of the jaws

2013

Limeres et al. [26]

IV

N/A

Spain/

N/A

RA

N/A

N/A

N/A

N/A

Oral self-mutilation (including auto-extraction of teeth)

2012

Mass [70]

III

IKBKAP

N/A /

N/A

RA

N/A

N/A

N/A

Insensitivity to pain and temperature, vasomotor instability, respiratory distress, orthostatic hypotension, insensitivity to hypoxia, decreased deep tendon reflexes, alacrima

Absence of fungiform papilla, dental traumata, orofacial self-mutilation, proportionally small jaws, crowding of teeth, low caries rate, hypersalivation, impaired taste sensation

2003

Nagasako et al. [71]

HSAN IV

N/A

USA/

N/A

RA

N/A

N/A

N/A

Insensitivity to pain, self-mutilation, painless fractures, fever, hypohidrosis

Orofacial self-mutilation

CR case report, CS case series, F female, G gender, GA genetics article, HA histological article, IKBKAP inhibitor of kappa light polypeptide gene enhancer in B-cells kinase complex-associated protein, Inter international, m month(s), M male, N number of patients, N/A not available, NGFB nerve growth factor (beta polypeptide), NTRK1 neurotrophic tyrosine kinase-1 receptor, PRDM12 PR domain-containing protein 12, Pub. publication, RA review article, Ts type of study, y year(s), UK United Kingdom, USA United States of America

Case presentation

An 8-month-old white boy of Turkish origin initially presented to the Department of Pedodontics, at Charité – Universitätsmedizin Berlin Hospital, due to an unexplained early loss of his primary lower central incisors. He was the first child of healthy consanguineous parents (second-degree relatives); their younger daughter was healthy. Our patient had multiple injuries on his face and body and in his oral cavity due to self-mutilation (Fig. 1). Further medical history revealed that he was born with a bilateral foot deformity (Fig. 2), which resulted in the mandatory use of an orthopedic appliance, enabling him to walk normally (Fig. 3). At the age of 6 years and 2 months, he had a fracture in the metatarsal bone, leading to bone necrosis. This resulted in the placement of bone plates and the use of a wheelchair for long walking distances. He had several accidents, such as severe burns from boiling water without feeling any pain.
Fig. 1

Representation of self-mutilation. a+b Extraoral self-mutilation. c+d Intraoral self-mutilation

Fig. 2

Bilateral bone deformity of the feet. a Clinical presentation of the deformed feet. b Radiographic presentation of the deformed feet

Fig. 3

Orthopedic appliance used to support the patient’s feet during walking. a+c Orthopedic appliance. b+d Patient wearing his orthodontic appliance

Prior to the first visit to the Department of Pedodontics at the age of 8 months, he had lost both mandibular primary central incisors for unknown reasons only 3 months after they erupted. His mandibular left lateral incisor was loose (mobility, grade 2). In addition, his mandibular left primary second molar (75) showed signs of enamel hypoplasia. He experienced no pain or discomfort during the dental procedures. A year later, he presented at our department due to the further loss of ten of his primary teeth (Fig. 4). The early loss of so many teeth raised suspicion of a systemic disorder. He was referred to the Department of Human Genetics at Charité – Universitätsmedizin Berlin. The following differential diagnoses of auto-aggression syndromes were suspected: congenital insensitivity to pain and anhidrosis (CIPA), Smith–Magenis syndrome, Lesch–Nyhan syndrome, or pantothenate kinase-associated neurodegeneration (PKAN). In addition, the following systemic diseases, which might cause premature loss of teeth, were suspected: Langerhans cell histiocytosis, hypophosphatasia, and Papillon–Lefèvre syndrome. The diagnosis of CIPA syndrome was thought to be closest to his condition. All other suspected auto-aggression syndromes and systemic diseases were excluded based on blood tests, genetic diagnosis, and further clinical examination. However, after deeper investigations, the diagnosis HSAN-VIII was considered the definitive diagnosis of our patient.
Fig. 4

Auto-extracted teeth of the patient

Partial dentures for maxilla and mandible were constructed to prevent speech impairment and to enhance his lower facial height (Fig. 5). Due to his high caries activity, an intensive prophylaxis program with continuous follow-up was implemented to avoid further dental deterioration and improve his oral health status. Over the years, with the help of an interdisciplinary medical team and his parents, he has shown great cooperation and completely ceased any sort of self-mutilation behavior.
Fig. 5

Prosthodontic treatment of the patient. (a+b) Intraoral pictures of patient without and with prostheses, respectively

Discussion

The pediatric dentist was the first to refer our patient to the human genetics department with the suspicion of HSAN syndrome, based on the premature loss of primary teeth and self-mutilation behavior. The initial diagnosis of our patient of CIPA or HSAN-IV was not confirmed by molecular analysis, since it did not detect a mutation in the neurotrophic tyrosine kinase-1 receptor gene (NTRK1), which is the receptor for nerve growth factor (NGF) related to CIPA syndrome [12]. Our patient harbored a homozygous mutation in the recently discovered gene PRDM12 [6]. Therefore, HSAN-VIII was his final diagnosis. Deoxyribonucleic acid (DNA) sequencing of the parents confirmed the segregation of the mutation in the family. The mode of inheritance was autosomal recessive [6]. Self-mutilation behavior is one of the most outstanding characteristics of HSAN syndrome. However, it is also common in other auto-aggression diseases, which makes the diagnosis challenging. Smith–Magenis syndrome was a differential diagnosis concerning the self-inflicted injuries [14], but a causative 17p.11.2 microdeletion was excluded by fluorescence in situ hybridization. As for Lesch–Nyhan syndrome, patients have dystonia and ballism [15], which were not symptoms of our patient. Further analysis did not reveal defects in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme, confirming the false diagnosis. PKAN is also characterized by dystonia and therefore was ruled out [1619]. Blood tests excluded the systemic diseases of Langerhans cell histiocytosis and hypophosphatasia [20]. Hypophosphatasia was also excluded because of our patient’s normal total serum alkaline phosphatase activity [2123]. Papillon–Lefèvre syndrome was not confirmed due to the absence of the diffuse palmoplantar hyperkeratosis and the progressive periodontitis [24]. Oral manifestations of HSAN are important, since they are one of the first complaints presented by affected patients. They can be detected early in life, starting with the eruption of the primary dentition [25]. Because of the variability and rarity of the clinical presentation of HSAN, no standard dental management protocols have been established. Patients with HSAN should be treated individually [26]. The dental treatment planning can be affected by several factors, such as age, mental development, and patient’s and parents’ compliance [27]. In the 1960s, the treatment approach for patients with HSAN was extraction of all primary teeth and construction of dentures in order to prevent self-mutilation. Nowadays, there are many dental treatment options for the prevention of self-mutilating behavior, varying from the elimination of sharp tooth surfaces by grinding or restoring them with resin composite, to the use of intraoral appliances such as mouthguards. Since the self-mutilation behavior of patients with HSAN-VIII starts in infancy, it may prove difficult to use intraoral appliances at that point. However, tooth extractions should be considered the last line of treatment. Early loss of teeth is one of the most frequent dental complications of HSAN. It is important to be able to deal with its consequences, such as speech impairment and increased incidence of malocclusions [25, 26, 28]. Professional dental cleaning, behavioral management, and routine check-up appointments were the cornerstones of our treatment plan. Prevention of dental disease is required in patients with HSAN, since caries progression and pulpal involvement can occur without causing any pain or discomfort. The parents of patients with HSAN play a crucial role in the management of the condition, since their psychological support is necessary to help the child understand his or her condition and prevent further injuries [27, 28]. The most critical phase of managing patients with HSAN would be building an understanding of the emotional experience of pain. A psychological approach should be introduced as early as possible [27]. Cognitive behavioral models for self-management and distress regulation have been proposed [29].

The literature search revealed that HSAN-IV (CIPA) is the most discussed form of HSAN in dentistry. Self-mutilation and auto-aggression are the first and most common clinical characteristics in all mentioned HSAN types (Table 2). The literature review results mainly consisted of case reports and case series, which is understandable due to the rarity of the syndrome. In contrast to our case report, a long follow-up period was not reported in the majority of publications. Our case report is, to the best of our knowledge, the first to discuss the oral manifestations and management of HSAN-VIII. Zhang et al. [30] also reported on the clinical characteristics of five patients with HSAN-VIII and was in line with Chen et al. [6]. The clinical characteristics described by Zhang et al. [30] that were found in all patients were: insensitivity to pain, normal neurological examinations and intellect, corneal abrasions, lack of tear production, recurrent infections, and unexplained oral self-mutilation (especially tongue injuries). There is a need for further dental and medical management solutions for these patients, as well as for well-educated practitioners [29]. There are many obstacles that have to be overcome since often there is a lack of resources for research and international collaboration and for accessible database and diagnostic and treatment tools. By expanding our knowledge on genetic and epigenetic factors that are critical for pain sensation, new fields are opened for therapeutic intervention in chronic and neuropathic pain conditions [6, 31, 32].

Conclusions

HSAN-VIII is a rare, complex, recently identified condition mainly characterized by insensitivity to pain and thermal stimuli. The affected persons are vulnerable to various complications and in severe cases, self-mutilation can lead to death. Early identification of the disease is important to prevent all these consequences. The literature contains mainly case reports and case series of patients with HSAN, therefore, there are many knowledge gaps concerning preventive and therapeutic approaches. Treatment efficacy depends on educating the family and supporting the child psychologically. Moreover, an interdisciplinary treatment approach, in which there is medical and dental interdisciplinary cooperation, is required for such patients. A homozygous mutation of the PRDM12 gene, which is responsible for the HSAN-VIII condition, was identified in our patient. Mutations in this gene cause developmental defects in sensory neurons before their transition to nociceptors.

Abbreviations

CIPA: 

Congenital insensitivity to pain and anhidrosis

HSAN-VIII: 

Hereditary sensory and autonomic neuropathy type VIII

NGF: 

Nerve growth factor

OMIM: 

Online Mendelian Inheritance in Man

NTRK1

Neurotrophic tyrosine kinase-1 receptor

PKAN: 

Pantothenate kinase-associated neurodegeneration

PRDM12

PR domain-containing protein 12 gene

Declarations

Acknowledgements

Not applicable.

Funding

This study was funded by the authors and their institutions.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Authors’ contributions

All authors have read and approved the final manuscript. LG is the human geneticist who did the genetic analysis and interpretation. CF, KE, and SR were the pediatric dentists of the patient. CF followed the dental treatment of the patient from 8 months of age until the present time. TB, PJ, and KE conceived and designed the work, reviewed the literature and the differential diagnosis, and delineated the critical point for the discussion. All the authors gave their contribution to the drafting and critical review of the article.

Ethics approval and consent to participate

No ethical approval was needed. Informed consent was obtained from the patient’s legal guardians involved in this study.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Center for Dental and Craniofacial Sciences, Department of Orthodontics, Dentofacial Orthopedics and Pedodontics, Charité – Universitätsmedizin Berlin
(2)
Ambulantes Gesundheitszentrum, Campus Virchow Clinic, Charité – Universitätsmedizin Berlin
(3)
Charité Campus Virchow, Department of Human Genetics, Charité – Universitätsmedizin Berlin

References

  1. Dearborn G. A case of congenital pure analgesia. J Nerv Ment Dis. 1932;75:612–5.View ArticleGoogle Scholar
  2. Dyck PJ, Mellinger JF, Reagan TJ, Horowitz SJ, McDonald JW, Litchy WJ, et al. Not 'indifference to pain' but varieties of hereditary sensory and autonomic neuropathy. Brain. 1983;106(Pt 2):373–90.View ArticlePubMedGoogle Scholar
  3. Rotthier A, Auer-Grumbach M, Janssens K, Baets J, Penno A, Almeida-Souza L, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010;87:513–22.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Yuan J, Matsuura E, Higuchi Y, Hashiguchi A, Nakamura T, Nozuma S, et al. Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation. Neurology. 2013;80:1641–9.View ArticlePubMedGoogle Scholar
  5. Haga N, Kubota M, Miwa Z. Japanese Research Group on Congenital Insensitivity to Pain. Hereditary sensory and autonomic neuropathy types IV and V in Japan. Pediatr Int. 2015;57:30–6.View ArticlePubMedGoogle Scholar
  6. Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, et al. Transcriptional regulator PRDM12 is essential for human pain perception. Nat Genet. 2015;47:803–8.View ArticlePubMedGoogle Scholar
  7. Amano A, Akiyama S, Ikeda M, Morisaki I. Oral manifestations of hereditary sensory and autonomic neuropathy type IV. Congenital insensitivity to pain with anhidrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86:425–31.View ArticlePubMedGoogle Scholar
  8. Gao L, Guo H, Ye N, Bai Y, Liu X, Yu P, et al. Oral and craniofacial manifestations and two novel missense mutations of the NTRK1 gene identified in the patient with congenital insensitivity to pain with anhidrosis. PLoS One. 2013;8:e66863.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Neves BG, Roza RT, Castro GF. Traumatic lesions from congenital insensitivity to pain with anhidrosis in a pediatric patient: dental management. Dent Traumatol. 2009;25:545–9.View ArticlePubMedGoogle Scholar
  10. Bodner L, Woldenberg Y, Pinsk V, Levy J. Orofacial manifestations of congenital insensitivity to pain with anhidrosis: a report of 24 cases. ASDC J Dent Child. 2002;69:293–6. 235.Google Scholar
  11. Ashwin DP, Chandan GD, Jasleen HK, Rajkumar GC, Rudresh KB, Prashanth R. Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature. Oral Maxillofac Surg. 2015;19:117–23.View ArticlePubMedGoogle Scholar
  12. Bonkowsky JL, Johnson J, Carey JC, Smith AG, Swoboda KJ. An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. Pediatrics. 2003;112:e237–41.View ArticlePubMedGoogle Scholar
  13. Ravichandra KS, Kandregula CR, Koya S, Lakhotia D. Congenital insensitivity to pain and anhydrosis: diagnostic and therapeutic dilemmas revisited. Int J Clin Pediatr Dent. 2015;8:75–81.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Girirajan S, Elsas LJ, Devriendt K, Elsea 2nd SH. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet. 2005;42:820–8.Google Scholar
  15. Pozzi M, Piccinini L, Gallo M, Motta F, Radice S, Clementi E. Treatment of motor and behavioural symptoms in three Lesch-Nyhan patients with intrathecal baclofen. Orphanet J Rare Dis. 2014;9:208.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Brunetti D, Dusi S, Morbin M, Uggetti A, Moda F, D'Amato I, et al. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum Mol Genet. 2012;21:5294–305.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Gregory A, Hayflick SJ, et al. Pantothenate Kinase-Associated Neurodegeneration. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, editors. GeneReviews(R). Seattle: University of Washington, Seattle University of Washington, Seattle; 1993. All rights reserved.Google Scholar
  18. Gregory A, Hayflick SJ. PANK2 mutation screening recommended to confirm diagnosis of pantothenate kinase-associated neurodegeneration. AJNR Am J Neuroradiol. 2006;27:951.PubMedGoogle Scholar
  19. Yapici Z, Akcakaya NH, Tekturk P, Iseri SA, Ozbek U. A novel gene mutation in PANK2 in a patient with severe jaw-opening dystonia. Brain Dev. 2016;38(8):755–8.View ArticlePubMedGoogle Scholar
  20. Calming U, Henter JI. Elevated erythrocyte sedimentation rate and thrombocytosis as possible indicators of active disease in Langerhans' cell histiocytosis. Acta Paediatr. 1998;87:1085–7.View ArticlePubMedGoogle Scholar
  21. Fraser D. Hypophosphatasia. Am J Med. 1957;22:730–46.View ArticlePubMedGoogle Scholar
  22. Jaruratanasirikul S, Chanvitan P. Hypophosphatasia: the importance of alkaline phosphatase in bone mineralization. J Med Assoc Thai. 1999;82:1268–72.PubMedGoogle Scholar
  23. Reibel A, Maniere MC, Clauss F, Droz D, Alembik Y, Mornet E, et al. Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet J Rare Dis. 2009;4:6.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Dhanrajani PJ. Papillon-Lefevre syndrome: clinical presentation and a brief review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:e1–7.View ArticlePubMedGoogle Scholar
  25. Butler J, Fleming P, Webb D. Congenital insensitivity to pain – review and report of a case with dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:58–62.View ArticlePubMedGoogle Scholar
  26. Limeres J, Feijoo JF, Baluja F, Seoane JM, Diniz M, Diz P. Oral self-injury: an update. Dent Traumatol. 2013;29:8–14.View ArticlePubMedGoogle Scholar
  27. Schalka MM, Correa MS, Ciamponi AL. Congenital insensitivity-to-pain with anhidrosis (CIPA): a case report with 4-year follow-up. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:769–73.View ArticlePubMedGoogle Scholar
  28. Kouvelas N, Terzoglou C. Congenital insensitivity to pain with anhidrosis: case report. Pediatr Dent. 1989;11:47–51.PubMedGoogle Scholar
  29. Graham CD, Gouick J, Krahe C, Gillanders D. A systematic review of the use of Acceptance and Commitment Therapy (ACT) in chronic disease and long-term conditions. Clin Psychol Rev. 2016;46:46–58.View ArticlePubMedGoogle Scholar
  30. Zhang S, Sharif SM, Chen YC, Valente EM, Ahmed M, Sheridan E, Bennett C, Woods G. Clinical features for diagnosis and management of patients with PRMD12 congenital insensitivity to pain. J Med Genet. 2016;53:533–5.View ArticlePubMedPubMed CentralGoogle Scholar
  31. Crow M, Denk F, McMahon SB. Genes and epigenetic processes as prospective pain targets. Genome Med. 2013;5:12.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Denk F, McMahon SB. Chronic pain: emerging evidence for the involvement of epigenetics. Neuron. 2012;73:435–44.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Haga N, Kubota M, Miwa Z. Epidemiology of hereditary sensory and autonomic neuropathy type IV and V in Japan. Am J Med Genet A. 2013;161A:871–4.View ArticlePubMedGoogle Scholar
  34. Rotthier A, Baets J, Timmerman V, Janssens K. Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol. 2012;8:73–85.View ArticlePubMedGoogle Scholar
  35. Kok C, Kennerson ML, Spring PJ, Ing AJ, Pollard JD, Nicholson GA. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet. 2003;73:632–7.View ArticlePubMedPubMed CentralGoogle Scholar
  36. Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010;285:11178–87.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Guelly C, Zhu PP, Leonardis L, Papic L, Zidar J, Schabhuttl M, et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011;88:99–105.View ArticlePubMedPubMed CentralGoogle Scholar
  38. Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011;43:595–600.View ArticlePubMedPubMed CentralGoogle Scholar
  39. Kornak U, Mademan I, Schinke M, Voigt M, Krawitz P, Hecht J, et al. Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3. Brain. 2014;137:683–92.View ArticlePubMedGoogle Scholar
  40. Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O'Driscoll M, Brais B, et al. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet. 2004;74:1064–73.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Ilgaz Aydinlar E, Rolfs A, Serteser M, Parman Y. Mutation in FAM134B causing hereditary sensory neuropathy with spasticity in a Turkish family. Muscle Nerve. 2014;49:774–5.View ArticlePubMedGoogle Scholar
  42. Riviere JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, et al. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011;89:219–30.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.View ArticlePubMedGoogle Scholar
  44. Guven Y, Altunoglu U, Aktoren O, Uyguner ZO, Kayserili H, Kaewkahya M, et al. Twins with hereditary sensory and autonomic neuropathy type IV with preserved periodontal sensation. Eur J Med Genet. 2014;57:240–6.View ArticlePubMedGoogle Scholar
  45. Hutton A, McKaig S. The dental management of a child with congenital insensitivity to pain. Dent Update. 2010;37:180–2. 185.Google Scholar
  46. Zilberman U, Zilberman S, Keinan D, Elyiahu M. Enamel development in primary molars from children with familial dysautonomia. Arch Oral Biol. 2010;55:907–12.View ArticlePubMedGoogle Scholar
  47. Singla S, Marwah N, Dutta S. Congenital insensitivity to pain (hereditary sensory and autonomic neuropathy type V): a rare case report. J Dent Child (Chic). 2008;75:207–11.Google Scholar
  48. Siqueira SR, Okada M, Lino AM, Teixeira MJ, Siqueira JT. Proposal for a standardized protocol for the systematic orofacial examination of patients with Hereditary Sensory Radicular Neuropathy. Int Endod J. 2006;39:905–15.View ArticlePubMedGoogle Scholar
  49. Erdem TL, Ozcan I, Ilguy D, Sirin S. Hereditary sensory and autonomic neuropathy: review and a case report with dental implications. J Oral Rehabil. 2000;27:180–3.View ArticlePubMedGoogle Scholar
  50. Kim JS, Woo YJ, Kim GM, Kim CJ, Ma JS, Hwang TJ, et al. Congenital insensitivity to pain with anhidrosis: a case report. J Korean Med Sci. 1999;14:460–4.View ArticlePubMedPubMed CentralGoogle Scholar
  51. Rodd HD, Loescher AR, Boissonade FM. Immunocytochemical and electron-microscopic features of tooth pulp innervation in hereditary sensory and autonomic neuropathy. Arch Oral Biol. 1998;43:445–54.View ArticlePubMedGoogle Scholar
  52. Mass E, Gadoth N, Harell D, Wolff A. Can salivary composition and high flow rate explain the low caries rate in children with familial dysautonomia? Pediatr Dent. 2002;24:581–6.PubMedGoogle Scholar
  53. Edvardson S, Cinnamon Y, Jalas C, Shaag A, Maayan C, Axelrod FB, et al. Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Ann Neurol. 2012;71:569–72.View ArticlePubMedGoogle Scholar
  54. Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet. 2013;45:1399–404.View ArticlePubMedGoogle Scholar
  55. Woods CG, Babiker MO, Horrocks I, Tolmie J, Kurth I. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur J Hum Genet. 2015;23:1434.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Eregowda NI, Yadav S, Parameshwarappa P, Basavraj RK. A Girl with No Pain: Congenital Insensitivity To Pain and Anhidrosis (HSAN) Type IV – A Case Report. J Clin Diagn Res. 2016;10:Zl01–02.Google Scholar
  57. Ozkaya AK, Guler E, Arik E, Namli AR, Cevizli D, Gungor O. A case of congenital insensitivity to pain with anhidrosis. Turk Pediatri Ars. 2014;49:177–9.View ArticlePubMedPubMed CentralGoogle Scholar
  58. Fruchtman Y, Perry ZH, Levy J. Morbidity characteristics of patients with congenital insensitivity to pain with anhidrosis (CIPA). J Pediatr Endocrinol Metab. 2013;26:325–32.View ArticlePubMedGoogle Scholar
  59. Paduano S, Iodice G, Farella M, Silva R, Michelotti A. Orthodontic treatment and management of limited mouth opening and oral lesions in a patient with congenital insensitivity to pain: case report. J Oral Rehabil. 2009;36:71–8.View ArticlePubMedGoogle Scholar
  60. Romero M, Simon R, Garcia-Recuero JI, Romance A. Dental management of oral self-mutilation in neurological patients: a case of congenital insensitivity to pain with anhidrosis. Med Oral Patol Oral Cir Bucal. 2008;13:E644–647.PubMedGoogle Scholar
  61. Wolff A, Harell D, Gadoth N, Mass E. Submandibular and sublingual salivary gland function in familial dysautonomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:315–9.View ArticlePubMedGoogle Scholar
  62. Theodorou SD, Klimentopoulou AE, Papalouka E. Congenital insensitivity to pain with anhidrosis. Report of a case and review of the literature. Acta Orthop Belg. 2000;66:137–45.PubMedGoogle Scholar
  63. Mass E, Brin I, Belostoky L, Maayan C, Gadoth N. A cephalometric evaluation of craniofacial morphology in familial dysautonomia. Cleft Palate Craniofac J. 1998;35:120–6.View ArticlePubMedGoogle Scholar
  64. Mass E, Zilberman U, Gadoth N. Abnormal enamel and pulp dimensions in familial dysautonomia. J Dent Res. 1996;75:1747–52.View ArticlePubMedGoogle Scholar
  65. Mass E, Gadoth N. Oro-dental self-mutilation in familial dysautonomia. J Oral Pathol Med. 1994;23:273–6.View ArticlePubMedGoogle Scholar
  66. Mass E, Sarnat H, Ram D, Gadoth N. Dental and oral findings in patients with familial dysautonomia. Oral Surg Oral Med Oral Pathol. 1992;74:305–11.View ArticlePubMedGoogle Scholar
  67. Brahim JS, Roberts MW, McDonald HD. Oral and maxillofacial complications associated with congenital sensory neuropathy with anhydrosis: report of two cases. J Oral Maxillofac Surg. 1987;45:331–4.View ArticlePubMedGoogle Scholar
  68. Thompson BH, Hartwell GR, Ekvall WM, Koudelka BM. Endodontic management of a patient with familial dysautonomia. J Endod. 1986;12:170–3.View ArticlePubMedGoogle Scholar
  69. Kumar A, Naik P, Jaishankar HP. Congenital insensitivity to pain: Review with dental implications. Indian J Pain. 2014;28:13.View ArticleGoogle Scholar
  70. Mass E. A review of the oro-dento-facial characteristics of hereditary sensory and autonomic neuropathy type III (familial dysautonomia). Spec Care Dentist. 2012;32:15–20.View ArticlePubMedGoogle Scholar
  71. Nagasako EM, Oaklander AL, Dworkin RH. Congenital insensitivity to pain: an update. Pain. 2003;101:213–9.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s). 2017

Advertisement