[논문]CEP290 돌연변이로 인해 발생한 Joubert 증후군 말기 신부전 1례

김성훈; 이상택; 성문우; 김만진; 이준화

CEP290 돌연변이로 인해 발생한 Joubert 증후군 말기 신부전 1례
A Case of End-Stage Renal Disease with Joubert Syndrome due to CEP290 Mutation 원문보기

대한유전성대사질환학회지 = Journal of the Korean Society of Inherited Metabolic Disease, v.20 no.1, 2020년, pp.29 - 35

김성훈 (성균관대학교 의과대학 삼성창원병원 소아청소년과) , 이상택 (성균관대학교 의과대학 삼성창원병원 소아청소년과) , 성문우 (서울대학교 의과대학 진단검사의학과) , 김만진 (서울대학교 의과대학 진단검사의학과) , 이준화 (성균관대학교 의과대학 삼성창원병원 소아청소년과)

초록
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쥬버트 증후군(JS, Joubert syndrome)은 대부분 상염색체 열성으로 유전되는 유전성 대사질환으로 임상증상은 신생아 시기부터 발현된다. 저자들은 신생아기부터 특징적인 임상 증상이 순차적으로 발현되어 임상적으로 JS를 의심하였으나 특징적인 뇌 MRI 소견인 molar tooth sign (MTS)이 늦게 나타난 후 전장엑솜분석(WES, whole exome sequencing)으로 확진 된, 말기 신부전을 동반한 JS 1례를 경험하였기에 보고하고자 한다. 14세 남자 환자는 출생 직후 반복적인 무호흡과 과호흡으로 치료받은 병력이 있으며, 생후 8개월때부터 전반적 발달 지연과 관련되어 처음 병원을 방문하여 기본적인 발달 지연에 관한 검사를 시행하였으나 특이 소견 없었고, 이후 15개월 때 근육생검을 포함한 여러 검사를 통해 사립체(mitochondrial) 질환으로 진단 되었었다. 이후 물리 치료만 하며 관찰 하던 중 안구진탕과 망막질환이 확인되었다. 생후 7세 8개월에는 처음 발작이 있었으며, 말기 신부전이 있어 8세부터 혈액투석을 시작한 후, 혈액 투석 직후 수차례 발작이 있었으나 전해질 불균형으로 인한 발작으로 진단하여 항뇌전증 약물 치료는 하지 않았다. 9세 4개월 때 고혈압으로 인한 뇌출혈로 치료 받았으며, 이때 시행한 뇌 CT상 MTS가 처음 의심되었다. 13세 10개월에 시행한 뇌 MRI 검사상 MTS가 명확히 확인되었고, 전장엑솜 분석으로 JS의 CEP290 mutation (c.6012-12T>A)이 확인되었다. 환자는 신생아기부터 발현된 특징적인 임상 소견과 말기 신부전 상태, 뇌 CT 또는 MRI소견, 그리고 전장엑솜분석 검사로 JS로 확진하였다. JS는 임상 양상이 다양할 뿐만 아니라 진단에 중요한 MTS 소견이 초기에 보이지 않더라도, 임상적으로 의심된다면 확진을 위해서 전장엑솜분석을 시행하는 것이 필요하다.

Abstract ▼ AI-Helper

Joubert syndrome (JS) is a rare genetic disorder that is characterized by ataxia, hypotonia, developmental delay, respiratory abnormalities such as apnea-hyperpnea, and abnormal eye movements. The pathognomonic diagnostic finding is the "molar tooth sign" (MTS) on brain magnetic resonance imaging (MRI), described as cerebellar vermis hypoplasia or dysplasia, thick and horizontally oriented superior cerebellar peduncles, and an abnormally deep interpeduncular fossa. JS is characterized by genetic heterogeneity: pathogenic variants in over 30 genes have been identified to date. The CEP290 protein, which is on chromosome 12q21.3, is most frequently mutated in patients with JS, especially with renal involvement. Here, we report a case of JS in a 14-year-old male patient with end-stage renal disease. To the best of our knowledge, this is the first Korean report of a patient with JS due to CEP290 mutation (c.6012-12T> A) whose diagnosis was confirmed after repetitive MRI. We suggest consultation with an experienced neuro-radiologist and follow-up MRI studies to detect a "hidden" MTS if clinical findings suggest a diagnosis of JS. Furthermore, even in the absence of an MTS, whole exome sequencing should be considered.

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표/그림 (3)

그림 Fig. 1. A photograph of the patient at 14 years in which he sat in a wheelchair due to global developmental delay (A). His facial photograph shows facial dysmorphisms, including prominent forehead, right-dominant bilateral ptosis, high rounded eyebrows, broad and shallow nasal bridge, lower lip eversion with trapezoid-shaped open mouth, and tongue protrusion (B). Publication of gross photos was permitted by his parents through informed consent.
그림 Fig. 2. At 9 years 4 months of age, the patient underwent brain computed tomography (CT) that showed intracranial hemorrhage, intraventricular hemorrhage, and midline shifting to the left side due to hypertension (A and B). The molar tooth sign (MTS) was observed on brain CT performed at 9 years 4 months of age (C) and on brain magnetic resonance imaging (MRI) at 12 years 2 months of age (D). Axial T2-weighted MRI shows an MTS appearance of the midbrain with thickened superior cerebellar peduncle (arrow) and vermian hypoplagia.
그림 Fig. 3. Identification of a c.6012-12T>A, homozygote mutation in CEP290 (NM_025114.3). The BAM file displayed in The Integrative Genomics Viewer (IGV) shows c.6012-12T>A, homozygote is indisputable in the forward (red in IGV) and reverse (blue in IGV) strands.

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제안 방법

The patient continued with rehabilitation treatment until he was 7 years 8 months old, when he returned to the hospital with his first afebrile seizure due to hyponatremia shortly after hemodialysis. At that time, electroencephalogram (EEG) test result was normal.
The patient started peritoneal dialysis at age 14 years 2 months, and he still uses a wheelchair for ambulation.

대상 데이터

2. At 9 years 4 months of age, the patient underwent brain computed tomography (CT) that showed intracranial hemorrhage, intraventricular hemorrhage, and midline shifting to the left side due to hypertension (A and B). The molar tooth sign (MTS) was observed on brain CT performed at 9 years 4 months of age (C) and on brain magnetic resonance imaging (MRI) at 12 years 2 months of age (D).
He also showed both corneal band keratopathy, corneal opacity and nystagmus in the ophthalmologic examination. The patient suffered intracranial hemorrhage at 9 years 4 months of age, with a systolic blood pressure of 190 mmHg during hemodialysis. At that time, MTS findings were suspected on brain computed tomography (CT), suggesting the possibility of JS, but genetic testing was not possible due to economic and other problems.
The patient was a male baby and the only child of a healthy 32-year-old mother and a healthy 33-year-old father, neither of whom had a family history of neurological or hereditary disorder. The patient weighed 3,700 g (90th percentile) at birth at a gestational age of 40 weeks by Cesarean section delivery due to cephalopelvic disproportion.

참고문헌 (19)

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