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Abstract：
BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability.
METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing.
RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation.
CONCLUSIONS: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.
METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing.
RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation.
CONCLUSIONS: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.
摘要：
背景：对无汗症疼痛的先天性不敏感（CIPA）是一种极为罕见的常染色体隐性遗传疾病，由NTRK1基因的功能丧失突变引起，影响自主神经和感觉神经系统.临床表现多样，包括反复发热，疼痛不敏感，无汗症,自残行为，智力残疾。
方法：使用外显子组或基因组测序，对两名男性和一名女性的临床和遗传特征进行了评估。
结果：CIPA症状包括反复发热，疼痛不敏感，1岁时表现为无汗症（年龄范围：0.3-8岁）。两名患者表现出自残倾向，智力残疾,和发育迟缓。四个NTRK1（NM_002529.3）突变，c.851-33T>A（p。?),c.2020G>T（p。Asp674Tyr),c.2303C>T（p。Pro768Leu),和c.574-156_850+1113del(外显子5-7del)被鉴定。两名患者表现出早期发作和严重的表型，为c.851-33T>A纯合（p。？）突变和c.851-33T>A的复合杂合（p。？）和c.2020G>T（p。Asp674Tyr)NTRK1的突变。第三位具有c.230C>T的复合杂合突变的患者（p。Pro768Leu）和c.574-156_8501113del（外显子5-7del）表现出迟发和温和的临床表现。
结论：所有3例患者均表现出不同的表型和疾病严重程度。这项研究丰富了我们对CIPA的临床和遗传方面的理解，突出可变的表型和疾病严重程度。
方法：使用外显子组或基因组测序，对两名男性和一名女性的临床和遗传特征进行了评估。
结果：CIPA症状包括反复发热，疼痛不敏感，1岁时表现为无汗症（年龄范围：0.3-8岁）。两名患者表现出自残倾向，智力残疾,和发育迟缓。四个NTRK1（NM_002529.3）突变，c.851-33T>A（p。?),c.2020G>T（p。Asp674Tyr),c.2303C>T（p。Pro768Leu),和c.574-156_850+1113del(外显子5-7del)被鉴定。两名患者表现出早期发作和严重的表型，为c.851-33T>A纯合（p。？）突变和c.851-33T>A的复合杂合（p。？）和c.2020G>T（p。Asp674Tyr)NTRK1的突变。第三位具有c.230C>T的复合杂合突变的患者（p。Pro768Leu）和c.574-156_8501113del（外显子5-7del）表现出迟发和温和的临床表现。
结论：所有3例患者均表现出不同的表型和疾病严重程度。这项研究丰富了我们对CIPA的临床和遗传方面的理解，突出可变的表型和疾病严重程度。
