CIPA was first described in 1932 [8, 9]. Since the pathogenic gene NTRK1 was first discovered and identified in 1996[4], 120 NTRK1 gene mutations have been recorded by HGMDpro [10]. NTRK1 gene contains 17 exons, code 796 amino acids [11]. The NTRK1 gene encodes tropomyosin receptor kinase A (TrkA), which is a high affinity receptor for nerve growth factor (NGF) [12]. The NGF-TRKA system regulates the growth and development of peripheral and central neurons, maintains the survival of neurons, and plays a key role in pain, itching, and inflammatory infections [13, 14]. Recent studies have found that NGF-TrkA is involved in vascularization and ossification of bone during embryonic development [15, 16].
The clinical manifestation of CIPA is recurrent fever in infant or early childhood due to anhidrosis, which is not sensitive to analgesic-antipyretic, but can be relieved by physical cooling, sometimes with epilepsy [17]. The other classic symptoms of CIPA are loss of algesthesis and inability to sweat [18]. Because of their insensitivity to pain, patients often show self-harm behaviors occurring in the soft tissues of the hands, lips and tongue [19]. In addition, patients are prone to repeated painless fractures and joint dislocations [20, 21]. Patients may still have psychomotor retardation, with an IQ of about 60 [22]. In this study, patient had recurrent fevers since birth which is not sensitive to analgesic-antipyretic. He bit his fingers and tongues after tooth eruption. His medical history revealed loss of algesthesis, inability to sweat, ulna fracture in right arm and dislocation of the left hip joint.
In this study, a compound heterozygous NTRK1 mutations (c.1750G > A; c.1769A > G) in the coding region of exon 13 of the NTRK1 gene (NM_001012331.1) was identified in the patient, which were inherited from his parents. The mutation c.1750G > A has previously been reported to be a pathogenic mutation. The maternal mutation c.1769A > G is a missense mutation which has not been previously reported (HGMD) and can lead to the aspartic acid changing into Glycine and has a great impact on the structure and function of the protein theoretically. According to the guide of ACMG gene mutation interpretation, this site was interpreted as a pathogenic mutation: no population carrying rate; the complex heterozygosis pathogenic mutation site has great influence on protein structure and function theoretically.
In conclusion, the novel mutation broaden the genetic mutation spectrum of NTRK1 in CIPA patients, and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA. But the in-depth study of this mutation pathogenic mechanism is needed to further clarify.