1例胱硫醚-β-合成酶基因缺乏致儿童静脉窦血栓病例分析

Analysis of A Child of Venous Sinus Thrombosis Caused by Cystathionine-β-Synthase Gene Deficiency

回顾性分析2020年7月广州医科大学附属广东省妇幼保健院收治的1例静脉窦血栓患儿病历资料,根据患儿临床表现、影像学特点及基因结果分析胱硫醚-β-合成酶(CBS)缺乏致儿童静脉窦血栓的临床特点及机制。6岁3个月男孩,间断头痛、呕吐1个月余,自3岁起出现轻度智力障碍、多动等表现,行走易摔跤。查体:胸廓呈漏斗状,平衡能力欠佳,单脚站立不稳。凝血功能国际标准化比值1.29[参考范围(0.82~1.15)],D二聚体559 ng/mL[参考范围21~243 ng/mL],血清同型半胱氨酸(Hcy)282.23μmol/L[参考范围5~15μmol/L]。头颅CT血管造影检查联合CT静脉成像、磁共振成像、血管磁共振成像均提示上矢状窦、大脑大静脉与直窦连接处、右侧颈内静脉等处多发低信号充盈缺损,考虑静脉血栓。患儿及父母基因检测结果显示,在CBS缺乏性高胱氨酸尿症相关的CBS基因上检出与受检者表型相关的两个致病变异,来自于母亲、父亲的异常基因结果分别为NM_000071.2:c.131delT(p.ILE44Thrfs*38)、NM_000071.2:c.919>A(p.G1y307Ser)变异,基因型均为杂合。予维生素B_(6)治疗后,患儿未再诉头痛,Hcy水平降低。当CBS基因缺乏或者突变时,其功能活性可能降低或丧失,从而导致Hcy血浆浓度升高,进一步导致血管系统疾病形成,临床常常表现为头痛、呕吐等。头部影像学常表现为血栓形成,且有家族基因缺陷,患儿父亲变异型基因符合常见血栓型变异基因G919A。患儿口服治疗剂量的维生素B6后,血清Hcy浓度持续下降,临床上未再发生头痛、呕吐等,远期效果仍需评估。

Objective: To retrospectively analyze the medical records of one child with venous sinus thrombosis admitted to Guangdong Maternal and Child Health Hospital Affiliated to Guangzhou Medical University in July 2020, and analyze the clinical features and mechanism of venous sinus thrombosis caused by cystathionine-β-synthase(CBS) deficiency in children according to clinical manifestations, imaging characteristics and gene results of the child. A boy aged 6 years and 3 months with intermittent headache and vomiting for more than 1 month has developed mild mental retardation and hyperactivity since the age of 3 years. He is easy to fall when walking. Physical examination: the thoracic cage is funnel-shaped, with poor balance and unstable standing on one foot. International normalized ratio of coagulation function is 1.29(reference range 0.82-1.15), D-dimer is 559 ng/m L(reference range 21-243 ng/m L), serum homocysteine(Hcy) is 282.23 μmol/L(reference range 5-15 μmol/L). Head CT angiography combined with CT venography, magnetic resonance imaging, and magnetic resonance venography all suggest multiple low signal filling defects in the superior sagittal sinus, the connection between the great cerebral vein and the straight sinus, and the right internal jugular vein. Venous thrombosis is considered. The gene test results of child and parents show that, two pathogenic variants related to the phenotype of the subjects are detected in the CBS gene related to CBS deficient homocystinuria. The abnormal genes from the mother and father are NM_000071.2: c. 131del T(p. ILE44Thrfs*38) and NM_000071.2: c. 919>A(p.G1y307Ser) variations, respectively. The genotypes are heterozygous. After vitamin B6 treatment, the child has no complain of headache and the level of Hcy decreases. When CBS gene is deficient or mutated, its functional activity may be reduced or lost,resulting in the increase of Hcy plasma concentration, which further leads to the formation of vascular system diseases. The clinical manifestations are often headache, vomiting and others. Head imaging often shows thrombosis with family gene defects. The variant gene of the child’s father is consistent with the common thrombotic variant gene G919A. After oral treatment of vitamin B6, the concentration of serum Hcy in child continues to decline, and there is no headache or vomiting in clinic. The long-term effect still needs to be evaluated.