Phenotypic heterogeneity of intellectual disability in patients with congenital insensitivity to pain with anhidrosis: A case report and literature review

Abstract

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive heterogeneous disorder mainly caused by mutations in the neurotrophic tyrosine receptor kinase 1 gene (NTRK1) and characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability. We herein report the first north Han Chinese patient with CIPA who exhibited classic phenotypic features and severe intellectual disability caused by a homozygous c.851-33T>A mutation of NTRK1, resulting in aberrant splicing and an open reading frame shift. We reviewed the literature and performed in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA. We found that intellectual disability was correlated with the specific Ntrk1 protein domain that a mutation jeopardized. Mutations located peripheral to the Ntrk1 protein do not influence important functional domains and tend to cause milder symptoms without intellectual disability. Mutations that involve critical amino acids in the protein are prone to cause severe symptoms, including intellectual disability.

Keywords

Congenital insensitivity to pain with anhidrosis genetics intellectual disability neurotrophic tyrosine receptor kinase 1 north Han Chinese

Introduction

Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy IV, is an autosomal recessive disorder caused by loss-of-function mutations in the neurotrophic tyrosine receptor kinase 1 gene (NTRK1, OMIM *191315),¹ nerve growth factor beta gene (NGFβ, OMIM *162030),^2,3 and necdin gene (NDN, OMIM *602117).⁴ The vast majority of mutations are observed in NTRK1.⁵ CIPA is characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability.^2,6 Classic symptoms of CIPA include recurrent unexplained fevers without sweating, self-mutilating behavior (e.g., biting of the tongue, lips, and distal extremities), recurrent bone fractures and Charcot arthropathy, nonhealing ulcers and injuries, and psychomotor retardation.^5,7,8 The pain insensitivity in patients with CIPA is caused by an absence of small-diameter thinly myelinated primary afferent or unmyelinated neurons, and the anhidrosis is caused by a deficiency of sympathetic postganglionic neurons.^5,9

Phenotypic heterogeneity in the occurrence of intellectual disability has been reported in patients with CIPA. Ntrk1-knockout mice lack basal forebrain cholinergic neurons and striatal cholinergic neurons.⁹ No autopsy data in humans with CIPA are available to validate these animal observations. Additionally, cranial magnetic resonance imaging has revealed no structural brain alterations in patients with CIPA.¹⁰ We herein present a case involving a patient with CIPA with classic phenotypic features and severe intellectual disability caused by a previously reported homozygous c.851-33T>A mutation of NTRK1 gene. We performed a literature review and in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA.

Methods

Patient

This study was approved by the Ethical Review Board of the Peking Union Medical College Hospital. Written informed consent was obtained from the patient’s parents.

A 27-year-old Han Chinese woman was referred to our hospital in 2013 and diagnosed with CIPA. Her clinical history was reviewed and a physical examination was performed. Her intelligence quotient was measured with the Wechsler Adult Intelligence Scale (WAIS IV, 2008 version). A nerve biopsy was not conducted because of the minimal benefit to the patient.

Genetic analysis

After obtaining informed consent, we drew 4 ml of peripheral blood from the patient and her parents. Genomic DNA was extracted with the TIANamp Genomic DNA Kit (Tiangen Biotech, Beijing, China) according to the manufacturer’s protocol.

All 17 exons and intron–exon boundaries were amplified by polymerase chain reaction (PCR) with primers used in previous reports.^6,11,12 Sanger sequencing was conducted by Berry Genomics Co., Ltd. (Beijing, China). The sequences were analyzed with Chromas software (version 2.1.1) and BLAT to UCSC Human Genome (Feb 2009, GRCh37/hg19, http://genome.ucsc.edu/) to call mutations.

The oligonucleotide-based comparative genomic hybridization (CGH) microarray is an efficient and reliable assay for copy number variation studies. The Agilent 1x1M Human Genome CGH microarray (Agilent, Santa Clara, CA, USA) was employed in this study. DNA processing, microarray handling, and data analysis were conducted by following the Agilent oligonucleotide array CGH protocol (version 6.0).

Literature review

The MeSH terms “congenital insensitivity to pain with anhidrosis” and “ntrk1 receptor” were used to search for articles pertinent to CIPA caused by NTRK1 mutation. Title and abstract screening was conducted to retrieve genetic studies, which elucidated genetic mutations causing CIPA. All mutations reported up to October 2017 were reviewed. Furthermore, using the known Ntrk1 protein structure (available at the RCSB Protein Data Bank, http://www.rcsb.org/pdb/home/home.do) and PyMOL software (Version 4.3.0), we attempted to interpret the heterogeneity of the intellectual disability in patients with CIPA.

Results

Clinical findings

The patient in the present case was a 27-year-old Han Chinese woman (Figure 1(a), III:3) born to nonconsanguineous parents (Figure 1(a), II:6 and II:7). Her mother had a history of a terminated pregnancy (Figure 1(a), III:1) and fetal death at 7 months of gestation (Figure 1(a), III:2). The proband had a 27-year history of anhidrosis and insensitivity to pain and had experienced recurrent unexplained fevers (maximum body temperature, 42°C) during her first year of life. Bilateral dislocation of the hip joints had been present since age 2 years. Although her body development was normal, she showed cognitive impairment at a young age. Self-mutilating behavior was first observed at age 6 years and resulted in finger, ankle, tibia, hip, and femur fractures. She developed osteomyelitis due to poor healing following trauma or surgical treatment of fractures. She required a wheelchair for ambulation because of deformation of her right hip joint, right knee, and left ankle (Figure 1(b)). Her intelligence quotient was about 44 (WAIS IV, 2008 version). She showed emotional instability and communication difficulty. The clinical characteristics of patients with CIPA with the hotspot c.851-33T>A mutation are summarized in Table 1.

Figure 1.

Patient’s pedigree and clinical and imaging characteristics. Panel A: Pedigree of the patient (P), who is indicated by an arrow. Panel B: Clinical characteristics and imaging of the proband. (a, b) Hypoplasia of the distal phalanges of both hands due to self-mutilation and osteomyelitis. (c) Deformity of the hip joint. (d–f) Malunion of the right knee. (g–i) Deformity and multiple fractures of the ankle and tibia. Panel C: Sequencing of NTRK1 reveals the homozygous c.851-33T>A mutation in the patient (P) and heterozygous c.851-33T>A mutation in her father (F) and mother (M).

Table 1.

Clinical characteristics of patients with CIPA with the c.851-33T>A mutation

Pt.	Genetic variants	Race	Sex	Age (y)	Insensitivity to pain	Charcot arthropathy	Recurrent bone fracture	Self-mutilation	Compromised proprioceptive sensation	Anhidrosis	Recurrent unexplained fever	Intellectual disability	Reference
1	Homo.	Chinese	F	27	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Present report
2	Homo.	Korean	M	28	Yes	NA	Yes	Yes	NA	Yes	NA	Yes	Nam et al., 2017¹³
3	Co.Het. and IVS14 + 3A>T	Korean	F	17	Yes	NA	Yes	Yes	NA	Yes	NA	Yes	Nam et al., 2017¹³
4	Co.Het. and IVS14 + 3A>T	Korean	F	16	Yes	NA	Yes	Yes	NA	Yes	NA	Yes	Nam et al., 2017¹³
5	Co.Het. and IVS14 + 3A>T	Korean	M	14	Yes	NA	Yes	Yes	NA	Yes	NA	Yes	Nam et al., 2017¹³
6	Co.Het. and c.2303C>T	Korean	M	16	No	No	Yes	No	No	NA	No	No	Jung et al., 2013¹⁴
7	Co.Het. and c.1415delG	Chinese	F	5	Yes	NA	NA	Yes	No	Yes	Yes	Yes	Li et al., 2012¹⁵
8	Homo.	Korean	M	2.7	Yes	NA	No	Yes	NA	Yes	Yes	Yes	Lee et al., 2009¹⁶
9	Co.Het. and NA	Korean	M	1.6	Yes	NA	No	Yes	NA	Yes	Yes	Yes	Lee et al., 2009¹⁶
10	Co.Het. and NA	Korean	F	2.4	Yes	NA	No	Yes	NA	Yes	Yes	Yes	Lee et al., 2009¹⁶
11	Co.Het. and NA	Chinese	M	20	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Guo et al., 2004¹⁷
12	Co.Het. and NA	Chinese	M	18	Yes	Yes	Yes	NA	Yes	Yes	Yes	Yes	Guo et al., 2004¹⁷
13	Co.Het. and c.2281C>T	Chinese	M	5.8	Yes	Yes	Yes	NA	NA	Yes	Yes	NA	Lv et al., 2017¹⁸
14	Co.Het. and c.1652delA	Chinese	M	20	Yes	Yes	Yes	NA	NA	Yes	Yes	NA	Lv et al., 2017¹⁸
15-19	Co.Het. and NA	Japanese	NA	NA	Yes	NA	NA	NA	NA	Yes	Yes	NA	Miura et al., 2000¹⁹

All patients had the c.851-33T>A mutation. Pt., patient; F, female; M, male; Homo., homozygous; Co.Het., compound heterozygous; NA ,not available.

Genetic analysis

PCR followed by Sanger sequencing of NTRK1 was completed. Because previous reports have indicated that point mutations in the intron cause abnormal splicing and resultant CIPA, we repeated the analysis and confirmed the presence of a homozygous c.851-33T>A mutation in intron 7 in the patient and a heterozygous c.851-33T>A mutation in both of her nonconsanguineous parents (Figure 1, Panel C). The CGH microarray showed no evidence of copy number variation in her genome (data not shown), validating the homozygosity of the c.851-33T>A mutation. This mutation was previously verified to result in aberrant splicing and a reading frame shift and can reportedly cause CIPA.^13–19 To our knowledge, this is the first reported patient homozygous for the c.851-33T>A mutation in the north Han Chinese population.

Literature review

Structure of Ntrk1 protein

Crystal structures of the extracellular and intracellular parts of the Ntrk1 protein were identified by Wehrman et al.²⁰ and Bertrand et al.,²¹, respectively (Figure 2). The Ntrk1 protein contains 796 amino acids and consists of three leucine-rich repeats, two immunoglobulin-like domains (Ig-C1 and Ig-C2), a transmembrane domain, an adenosine triphosphate (ATP) binding site, and a tyrosine kinase domain (TKD). Once the nerve growth factor (NGF) homodimer binds to Ntrk1, it causes Ntrk1 dimerization and autophosphorylation of tyrosine residues 675, 679, and 680.²² This initiates the cytoplasmic signaling cascade that is essential for the survival and growth of neurons.²³

Figure 2.

Whole structure of Ntrk1 dimer binding with NGF homodimer. Panel A: Front view. Panel B: Lateral view. Panel C: Details of the interfaces of the cytoplasmic domains and three tyrosine residues phosphorylated during signaling transduction. Stereo visualization is realized by shading the further parts of the molecule. Residue numbers were labeled approximately in Panel B. Dotted lines were drawn manually to connect the extracellular and intracellular portions because no exact crystal structure for the transmembrane domain is available. LRR, leucine-rich repeats; Ig-C1 and Ig-C2, immunoglobulin-like domains; NGF, nerve growth factor; CM, cytomembrane; ATP BS, adenosine triphosphate binding site; TKD, tyrosine kinase domain.

Heterogeneity of intellectual disability in patients with CIPA

According to our literature review, 90% (99/110) of previously reported patients with CIPA had documented intellectual disability. However, about 10% (11/110) of the patients did not have intellectual disability (44 additional patients with CIPA whose intellectual disability status was not mentioned in the literature were excluded from the statistical analysis). We attempted to determine whether an association exists among CIPA mutation, its effect on Ntrk1 protein, and the presence of intellectual disability (Table 2).

Table 2.

NTRK1 mutations reported in patients with CIPA with or without intellectual disability

Pt.	Mutations	Polyphen2 score and prediction*	SIFT score and prediction*	Patients’ information			Reference
Pt.	Mutations	Polyphen2 score and prediction*	SIFT score and prediction*	Race	Inheritance model	Intellectual disability	Reference
1	c.722T>C; p.Leu213Proc.1556delG; p.G519fs28X	1.000, Pr.D-	0.00, D-	American	Co.Het.	No	Bonkowsky et al., 2003²⁴
2	c.2347C>T; p.Arg760Trp^#c.2337C>G; p.Tyr756X^#	0.653, Po.D-	0.00, D-	Italy	Co.Het.	No	Indo, 2001²⁵
3	c.2303C>T; p.Pro767Leu^#c.1621G>C; p.Gly516Arg^#	1.000, Pr.D; 1.000, Pr.D	0.03, D; 0.23, T	Japanese	Co.Het.	No	Ohto et al., 2004²⁶
4	c.2303C>T; p.Pro767Leu^#c.1660delC; p.Arg554Gly fs104X	1.000, Pr.D-	0.03, D-	Japanese	Co.Het.	No	Tanaka et al., 2012²⁷
5	c.2303C>T; p. Pro767Leu^#c.851-33T>A	1.000, Pr.D-	0.03, D-	Korean	Co.Het.	No	Jung et al., 2013¹⁴
6	c.574 + 1G>Ac.2206-2A>G	–	–	Spanish	Co.Het.	No	Sarasola et al., 2011²⁸
7	c.1633–1G>T	-	-	Turkish	Homo.	No	Tuysuz et al., 2008¹⁰
8	c.1633–1G>T	-	-	Turkish	Homo.	Yes	Tuysuz et al., 2008¹⁰
9	c.G1247A; p.Glu388Lysc.C2429T; p.Gln782X	0.883, Po.D-	0.66, T-	Swedish	Co.Het.	Yes	Wieczorek et al., 2008²⁹
10	c.1561T>C; p.Phe520Leu^#c.2057G>A; p.Arg685His^#	0.993, Pr.D; 0.103, B	0.00, D; 0.00, D	Chinese	Co.Het.	Yes	Gao et al., 2013³⁰
11	c.1635G>C; p.Ala526Pro^#c.2197G>A; p.Gly713Asp^#	0.999, Pr.D; 1.000, Pr.D	0.13, T; 0.00, D	Chinese	Co.Het.	Yes	Wang et al., 2015³¹
12	c.1715T>G; p.Ile571Ser^#	1.000, Pr.D	0.00, D	Turkish	Homo.	Yes	Li et al., 2012¹⁵
13	c.1825A>G; Met586Val^#	0.987, Pr.D	0.01, D	Japanese	Homo.	Yes	Yotsumoto et al., 1999³²
14	c.1945C>T; Arg648Trp^#c.44G>A; Trp15X	1.000, Pr.D-	0.00, D-	Chinese	Co.Het.	Yes	Li et al., 2012¹⁵
15	c.2001C>T; p.Arg653Cys^#	0.989, Pr.D	0.00, D	Turkish	Homo.	Yes	Guven et al., 2014³³
16	c.2150C>T; Pro689Leu	1.000, Pr.D	0.00, D	Israeli	Homo.	Yes	Shatzky et al., 2000³⁴
17	c.2209G>C; Val709Leu^#c.2236G>A; Glu718Ser^#	No Data; 0.997, Pr.D	0.33, T; 0.01, D	Malaysia	Co. Het.	Yes	Shalimar et al., 2007³⁵
18	c.2150T>G; p.Leu716Arg^#c.1672C>T; p.Gln557X^#	0.999, Pr.D-	0.00, D-	French	Co.Het.	Yes	Huehne et al., 2008³⁶
19	c.2155G>A; p.Glu718Lys^#c.287 + 2dupT	0.995, Pr.D-	0.00, D-	Korean	Co.Het.	Yes	Lee et al., 2009¹⁶
20	c.2206-11G>A; p.Glu734_Ala735insTrpProGln^#	–	–	Turkish	Homo.	Yes	Yis et al., 2015³⁷
21	c.783_785delGAA; p. 261delLys	-	-	Saudi	Homo.	Yes	Algahtani et al., 2016³⁸
22	c.1970T>C; p.Leu657Pro	0.786, Po.D	0.00, D	Pakistani	Homo.	Yes	Shaikh et al., 2017³⁹
23	c.2311C>T; p.Arg771Cys	1.000, Pr.D	0.00, D	Indian	Homo.	Yes	Shaikh et al., 2017³⁹
24	c.963delG; p.Leu322Serfs*148c.851-33T>A	–	–	Chinese	Co.Het.	Yes	Wang et al., 2016⁴⁰
25	c.1786G>A; p.Asp596Asnc.2350_2363del; p.Leu784Serfs*79	0.999, Pr.D-	0.10, T-	Korean	Co.Het.	Yes	Nam et al., 2017¹³
26	c.704C>G; p.Ser235*c.2020G>T, p.Asp674Tyr	-0.879, Po.D	-0.00, D	Korean	Co.Het.	Yes	Nam et al., 2017¹³

CIPA, congenital insensitivity to pain with anhidrosis; Pt., patient; Homo., homozygous; Co.Het., compound heterozygous; Pr.D, probably damaging; Po.D, possibly damaging; D, damaging; T, tolerated; B, benign

Notes: Patients who were Homo. or Co.Het. with frameshift mutations, premature stop mutations, and verified splice site mutations were not included in this table because of their highly deleterious effect with all patients exhibiting intellectual disability.

*Polyphen2 and SIFT scores and predictions (Pr.D, Po.D, D, T, and B) are given only for missense mutation. Discordances (patients without intellectual disability who had highly deleterious missense mutations or those with intellectual disability who had at least one possibly damaging or tolerable mutation) are in italics.

Because of the alternative splicing of NTRK1, different nomination systems were employed among the literature. Here, we mapped these mutations to the protein structure, in which the residue number may differ from that in the corresponding article.

-Data not available for frameshift or intron mutations.

In silico investigation of heterogeneity

We hypothesized that if the mutation on one of the two NTRK1 alleles is benign or tolerable, the patient may have less severe symptoms. We used the Polyphen2 (Harvard Medical School, Boston, MA, USA; http://genetics.bwh.harvard.edu/pph2/) and SIFT (J. Craig Venter Institute, La Jolla, CA, USA; http://sift.jcvi.org/) scores to predict the influence of a mutation. As shown in Table 2, these predictions were not correlated with the patients’ phenotype with respect to intellectual disability, as shown in italics. We then examined whether any observable association was present between the mutations and intellectual disability with an available Ntrk1 protein structure.

Figure 3(a) shows missense mutations (Table 2, Patients 1–5) in patients with CIPA without intellectual disability. As shown in the table, the point mutations p.Leu213Pro, Arg760Trp, and p.Pro767Leu were all located peripherally without apparent involvement in NGF binding, ATP binding, or interfaces of the TKD. In addition, leucine and proline are of similar structure with respect to their nonpolar side chains, which may have less effect on protein function. Because CIPA is a recessive disease, one copy of near fully functional genes will relieve the patient’s symptoms. The premature stop mutation p.Tyr756Ter caused Ntrk1 protein truncation of 40 amino acids at the C-terminal. This part of the Ntrk1 protein is located at a region distal to the kinase interface, which may be another reason that these children were not intellectually compromised.

Figure 3.

Observable association between mutations and the presence of intellectual disability. Panel A: At least one mutation reported in patients with CIPA without intellectual disability involved peripheral amino acids of the Ntrk1 protein. Panel B: Missense mutations in patients with CIPA with intellectual disability altered critical domains of the Ntrk1 protein. (Rotated by about 20º clockwise from the front view.)

Figure 3(b) shows missense mutations (Table 2, Patients 9–20) in patients with CIPA with apparent intellectual disability. All mutations were located in the functional domains; i.e., NFG binding site, ATP binding site, and interfaces of the TKD. Thus, we conclude that mutations located in functional domains of NTRK1 contribute to the observed intellectual disability.

In the present case, the c.851-33T>A mutation of NTRK1 caused a frame shift after the 283rd amino acid and a premature stop codon at the 319th codon,⁴¹ deleting the whole transmembrane domain, ATP binding site, and TKD. This mutation is highly deleterious and would be expected to cause intellectual disability in this patient.

Discussion

To our knowledge, this is the first case of CIPA in a north Han Chinese patient caused by a homozygous c.851-33T>A mutation that resulted in aberrant splicing and an open reading frame shift. We also reviewed all published Ntrk1 CIPA mutations in the literature and postulate that the presence of intellectual disability is determined by the location of the Ntrk1 mutation with respect to the functional protein domain. Missense mutations located peripheral to the Ntrk1 protein that do not jeopardize important domains (i.e., NGF binding site, ATP binding site, and TKD) tend to cause milder symptoms, usually without intellectual disability. Frame shift mutations, premature stop mutations, splice site mutations, and missense mutations that involve critical amino acids in the protein all cause severe intellectual disability.

However, several reports appear to be discordant. Sarasola et al.²⁸ described a 6-year-old Spanish girl with c.574 + 1G>A and c.2206-2A>G compound heterozygous mutations (Table 2, Patient 6) who was cognitively normal. The author verified the influence of the two splice site mutations with reverse transcription PCR. The c.574 + 1G>A mutation caused exon 5 skipping and predicted Ntrk1 protein truncation after residue 164. The c.2206-2A>G mutation caused two alternative splicings, and the predicted proteins were Ala736_Gln742 interstitial deletion and truncation after residue 735, respectively. Tuysuz et al.¹⁰ reported three Turkish patients with CIPA with a homozygous c.1633–1G>T mutation, one 2.5-year-old boy without psychomotor retardation, and one 14-year-old boy and one 8-year-old girl with psychomotor retardation (Table 2, Patients 7 and 8). This discrepancy indicates that there may be other factors modifying the phenotypes of CIPA. The functional impact of the variant, including dimerization, autophosphorylation, PLCγ activity, and toxicity of the mutated protein to the cell should be validated to confirm the pathogenicity of the variant.

Conclusions

In this study, we observed that intellectual disability in patients with CIPA appears to be determined by which Ntrk1 protein domain a mutation has jeopardized. Although this observation method is qualitative, it provides another alternative to evaluate the function of a missense mutation in addition to the Polyphen2 and SIFT scores. We are awaiting the delineation of additional cases of CIPA to provide additional evidence supporting our observations.

Footnotes

Acknowledgments

The authors thank Dr. Uluc Yis from the Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylul University, Izmir, Turkey for sharing their full-text article, which added rationality to our analysis.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research was funded by the National Natural Science Foundation of China (81501852, 81472046, 81472045), Beijing Natural Science Foundation (7172175), Beijing Nova Program (Z161100004916123), Beijing Nova Program Interdisciplinary Collaborative Project (xxjc201717), 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine, The Central Level Public Interest Program for Scientific Research Institute (2016ZX310177), PUMC Youth Fund & the Fundamental Research Funds for the Central Universities (3332016006), CAMS Initiative Fund for Medical Sciences (2016-I2M-3-003, 2016-I2M-2-006), the Distinguished Youth Foundation of Peking Union Medical College Hospital (JQ201506), and the 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.1).

References

Axelrod

Chelimsky

Weese-Mayer

DE.

Pediatric autonomic disorders.

Pediatrics 2006; 118: 309–321.

Indo

Tsuruta

Hayashida

et al . Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 1996; 13: 485–488.

Einarsdottir

Carlsson

Minde

et al . A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 2004; 13: 799–805.

Kuwako

Hosokawa

Nishimura

et al . Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival. J Neurosci 2005; 25: 7090–7099.

Indo

Nerve growth factor and the physiology of pain: lessons from congenital insensitivity to pain with anhidrosis.

Clin Genet 2012; 82: 341–350.

Mardy

Miura

Endo

et al . Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Am J Hum Genet 1999; 64: 1570–1579.

Bar-On

Weigl

Parvari

et al . Congenital insensitivity to pain. Orthopaedic manifestations. J Bone Jt Surg Br 2002; 84: 252–257.

Amano

Akiyama

Ikeda

et al . 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: 425–431.

Gabreels-Festin

Hereditary neuropathies in childhood: morphologic hallmarks and pathophysiologic mechanisms. J Child Neurol 1999; 14: 52–53.

10.

Tuysuz

Bayrakli

DiLuna

et al . Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population. Neurogenetics 2008; 9: 119–125.

11.

Verpoorten

Claeys

Deprez

et al . Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV. Neuromuscul Disord 2006; 16: 19–25.

12.

Liu

et al . Novel NTRK1 Frameshift Mutation in Congenital Insensitivity to Pain With Anhidrosis. J Child Neurol 2015; 30: 1357–1361.

13.

Nam

Yoon

et al . Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies. J Peripher Nerv Syst 2017; 22: 92–99.

14.

Jung

Kim

et al . Atypical hereditary sensory and autonomic neuropathy type IV with neither mental retardation nor pain insensitivity. J Child Neurol 2013; 28: 1668–1672.

15.

Liang

Sun

et al . Novel nonsense and frameshift NTRK1 gene mutations in Chinese patients with congenital insensitivity to pain with anhidrosis. Genet Mol Res 2012; 11: 2156–2162.

16.

Lee

et al . Clinical and genetic analysis of Korean patients with congenital insensitivity to pain with anhidrosis. Muscle Nerve 2009; 40: 855–859.

17.

Guo

Liao

Soong

et al . Congenital insensitivity to pain with anhidrosis in Taiwan: a morphometric and genetic study. Eur Neurol 2004; 51: 206–214.

18.

X jie

Song

Y wen

et al . Recurrent and novel mutations in the NTRK1 gene lead to rare congenital insensitivity to pain with anhidrosis in two Chinese patients. Clin Chim Acta 2017; 468: 39–45.

19.

Miura

Mardy

Awaya

et al . Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet 2000; 106: 116–124.

20.

Wehrman

Raab

et al . Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron 2007; 53: 25–38.

21.

Bertrand

Kothe

Liu

et al . The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J Mol Biol 2012; 423: 439–453.

22.

Stephens

Loeb

Copeland

et al . Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron 1994; 12: 691–705.

23.

Reichardt

LF.

Neurotrophin-regulated signalling pathways.

Philos Trans R Soc L B Biol Sci 2006; 361: 1545–1564.

24.

Bonkowsky

Johnson

Carey

et al . 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(3 Pt 2): e237–e241.

25.

Indo

Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.

Hum Mutat 2001; 18: 462–471.

26.

Ohto

Iwasaki

Fujiwara

et al . The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene. Neuropediatrics 2004; 35: 274–278.

27.

Tanaka

Satoh

Tanaka

et al . Congenital insensitivity to pain with anhidrosis: a case with preserved itch sensation to histamine and partial pain sensation. Br J Dermatol 2012; 166: 888–891.

28.

Sarasola

Rodriguez

Garrote

et al . A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis. BMC Med Genet 2011; 12: 86.

29.

Wieczorek

Bergstrom

Saaf

et al . Expanded HSAN4 phenotype associated with two novel mutations in NTRK1. Neuromuscul Disord 2008; 18: 681–684.

30.

Gao

Guo

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.

31.

Wang

Guo

Duan

et al . Novel and novel de novo mutations in NTRK1 associated with congenital insensitivity to pain with anhidrosis: a case report. Med 2015; 94: e871.

32.

Yotsumoto

Setoyama

Hozumi

et al . A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis. J Invest Dermatol 1999; 112: 810–814.

33.

Guven

Altunoglu

Aktoren

et al . Twins with hereditary sensory and autonomic neuropathy type IV with preserved periodontal sensation. Eur J Med Genet 2014; 57: 240–246.

34.

Shatzky

Moses

Levy

et al . Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet 2000; 92: 353–360.

35.

Shalimar

Sharaf

Farah

et al . Congenital insensitivity to pain with anhydrosis in a Malaysian family: a genetic analysis. J Orthop Surg (Hong Kong) 2007; 15: 357–360.

36.

Huehne

Zweier

Raab

et al . Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromuscul Disord 2008; 18: 159–166.

37.

Yis

Mademan

Kavukcu

et al . A novel NTRK1 mutation in a patient with congenital insensitivity to pain with anhidrosis. Acta Neurol Belg 2015; 115: 509–511.

38.

Algahtani

Naseer

Al-Qahtani

et al . Congenital insensitivity to pain with anhidrosis: A report of two siblings with a novel mutation in (TrkA) NTRK1 gene in a Saudi family. J Neurol Sci 2016; 370: 35–38.

39.

Shaikh

Chen

Halsall

et al . A Comprehensive Functional Analysis of NTRK1 Missense Mutations Causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV). Hum Mutat 2017; 38: 55–63.

40.

Wang

Guo

Duan

et al . Phenotypes and Genotypes in Five Children with Congenital Insensitivity to Pain with Anhidrosis. Pediatr Neurol 2016; 61: 63–69.

41.

Miura

Hiura

Torigoe

et al . Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis. Hum Genet 2000; 107: 205–209.