Atypical Presentation of Congenital Insensitivity to Pain With Anhidrosis Leading to Diagnostic Odyssey.

IF 1.5 4区 医学 Q4 GENETICS & HEREDITY Molecular Genetics & Genomic Medicine Pub Date : 2024-10-01 DOI:10.1002/mgg3.70027
Tomoyasu Higashimoto, Martin E Garber, Lauren Hipp, Jenna Damon, Qing Li
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Abstract

Background: Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal-recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV). The most commonly reported features include anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain.

Methods: We present a case of a 46-year-old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing.

Results: The patient (46-year-old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 - 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re-classified as likely pathogenic. The patient was started on a biologic disease-modifying anti-rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.

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先天性疼痛不敏感伴多汗症的非典型表现导致诊断难题。
背景:先天性痛觉不敏感伴潮湿症(CIPA)(OMIM 256800)是一种罕见的常染色体隐性遗传病,又称遗传性感觉和自主神经病变 IV 型(HSAN-IV)。最常报道的特征包括无汗症、智力障碍、自残、发热、温度感知受损、反复感染和/或自主神经系统受损。由于对关节疼痛不敏感,CIPA 患者也会出现被称为夏科(神经病理性)关节的主要关节破坏和关节畸形:我们介绍了一例 46 岁女性 CIPA 患者,她患有已知的 NTRK1 变异和之前未发现的变异。我们利用参考序列生成了包含 NTRK1 基因第 8 号外显子至第 13 号外显子的迷你基因报告构建体,其中一个报告构建体携带在我们的病例中发现的 c.1483 + 5G > A 变异。将迷你基因构建体转染到 HEK293T 细胞中,并对转录本进行剪接分析,以评估该变异对剪接的影响:患者(46 岁,女性)在 5 岁左右出现右踝关节畸形。患者成年后还出现腰椎压迫和膝关节损伤。她接受了大量的评估,但没有得到明确诊断。她的表现缺乏 CIPA 的许多常见临床表现,因此,评估的重点是她无法解释的关节畸形。外显子组测序发现了一个已知的NTRK1致病变异体(c.851 - 33T > A:p.? [Intron 7])和一个新的NTRK1变异体(c.1483 + 5G > A:p.? [Intron 11]),后被重新归类为可能致病。由于患者关节畸形的病因可能是炎症,因此开始使用生物改良抗风湿药物(bDMARD)。通过分子诊断,她的治疗和监测策略得以调整。我们的微型基因剪接分析表明,c.1483 + 5G > A 变体的存在对剪接有负面影响,支持了这一新型变体的致病性。
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来源期刊
Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.20
自引率
0.00%
发文量
241
审稿时长
14 weeks
期刊介绍: Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.
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