背景:关节,肾功能不全,和胆汁淤积综合征(ARCS)是一种罕见的常染色体隐性遗传疾病,由VPS33B(ARCS1)和VIPAS39(ARCS2)突变引起。根据文学,大多数ARCS患者在1岁时死于持续性感染和出血.我们报告了日本首例ARCS1和ARCS2患者,表现为轻度表型并通过基因检测诊断。
方法:案例1:一个6岁男孩,出生在非血缘关系的日本父母,表现为黄疸,血清γ-谷氨酰转移酶(GGT)水平正常,蛋白尿,双侧神经性耳聋,电机延迟,未能茁壮成长,和持续性瘙痒。2岁耳聋人工耳蜗植入术后,尽管血小板计数和凝血酶原时间-国际标准化比率正常,患者出现持续性出血,需要清除血肿.尽管他没有表现出任何明显的关节病迹象,根据其他症状,他被怀疑患有ARCS。使用靶向下一代测序(NGS)鉴定VPS33B中的复合杂合突变,这导致没有蛋白质表达。案例2:一个7个月大的男孩,病例1的弟弟表现为双侧耳聋,肾小管功能障碍,未能茁壮成长,轻度胆汁淤积.他的突变与他兄弟的VPS33B相同。案例3:一名24岁的男性出生在非血缘关系的日本父母被怀疑在他的童年时期患有进行性家族性肝内胆汁淤积1(PFIC1),其基础是低GGT胆汁淤积,肾小管功能障碍,感觉性耳聋,智力迟钝,和持续的瘙痒。在16岁时进行的肝活检显示与PFIC1一致的发现。活检后第二天,他因外周肝内动脉的腹膜内出血而出现贫血,需要经导管动脉栓塞术。ARCS2使用靶向NGS诊断,鉴定了VIPAS39中的新型复合杂合突变。
结论:本研究报告了使用基因检测诊断的日本首例ARCS1和ARCS2病例。这些病例比以前报告的病例温和。对于ARCS患者,侵入性手术应进行细致的护理,以防止出血。
BACKGROUND: Arthrogryposis, renal dysfunction, and cholestasis syndrome (ARCS) is a rare autosomal recessive disorder caused by mutations in VPS33B (ARCS1) and VIPAS39 (ARCS2). As per literature, most patients with ARCS died of persistent infections and bleeding by the age of 1 year. We report the first Japanese cases with ARCS1 and ARCS2 who presented with mild phenotypes and were diagnosed via genetic testing.
METHODS: Case 1: A 6-year-old boy born to nonconsanguineous Japanese parents presented with jaundice and normal serum gamma-glutamyl transferase (GGT) levels, proteinuria, bilateral nerve deafness, motor delay, failure to thrive, and persistent pruritus. After cochlear implantation for deafness at the age of 2 years, despite a normal platelet count and prothrombin time-international normalized ratio, the patient presented with persistent bleeding that required hematoma removal. Although he did not show any obvious signs of arthrogryposis, he was suspected to have ARCS based on other symptoms. Compound heterozygous mutations in VPS33B were identified using targeted next-generation sequencing (NGS), which resulted in no protein expression. Case 2: A 7-month-old boy, the younger brother of case 1, presented with bilateral deafness, renal tubular dysfunction, failure to thrive, and mild cholestasis. He had the same mutations that were identified in his brother\'s VPS33B. Case 3: A 24-year-old man born to nonconsanguineous Japanese parents was suspected to have progressive familial intrahepatic cholestasis 1 (PFIC1) in his childhood on the basis of low GGT cholestasis, renal tubular dysfunction, sensory deafness, mental retardation, and persistent itching. A liver biopsy performed at the age of 16 years showed findings that were consistent with PFIC1. He developed anemia owing to intraperitoneal hemorrhage from a peripheral intrahepatic artery the day after the biopsy, and transcatheter arterial embolization was required. ARCS2 was diagnosed using targeted NGS, which identified novel compound heterozygous mutations in VIPAS39.
CONCLUSIONS: The first Japanese cases of ARCS1 and ARCS2 diagnosed using genetic tests were reported in this study. These cases are milder than those previously reported. For patients with ARCS, invasive procedures should be performed with meticulous care to prevent bleeding.