Dimmock David, Kobayashi Keiko, Iijima Mikio, Tabata Ayako, Wong Lee-Jun, Saheki Takeyori, Lee Brendan, Scaglia Fernando
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Pediatrics. 2007 Mar;119(3):e773-7. doi: 10.1542/peds.2006-1950.
The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.
先证者在孕36周时出生，出生体重与孕周相符，其父母为非近亲结婚的白人。新生儿期无高胆红素血症或肝内胆汁淤积的证据，新生儿筛查结果正常。她曾出现3次危及生命的出血和贫血。对其出血素质的诊断评估显示凝血指标异常，无肝细胞损伤的生化证据。偶然发现她有严重的生长发育迟缓，对每天502千焦/千克（120千卡/千克）的蛋白质水解配方奶无反应。对生长发育不良进行了广泛的诊断检查，其他方面均正常，包括血浆氨基酸分析，结果显示高谷氨酰胺血症，瓜氨酸水平在参考范围内。复测样本检测显示孤立性高瓜氨酸血症。未检测到精氨琥珀酸。她的氨水平和尿乳清酸在参考范围内。随后的血浆氨基酸分析显示出一种提示由citrin缺乏引起的新生儿肝内胆汁淤积的特征，瓜氨酸、蛋氨酸和苏氨酸升高。成纤维细胞的蛋白质印迹法显示citrin缺乏，在患者SLC25A13基因的编码DNA中发现外显子3缺失。根据对患有这种疾病的成年人的经验，给患者提供了高蛋白、低碳水化合物饮食。生长发育不良和出血素质得到缓解。当放松对饮食处方的依从性时，再次出现生长发育迟缓，尽管未再次发生严重出血。这是首例关于北欧血统婴儿citrin缺乏的报告。出现生长发育不良和出血素质的年龄较晚，且无明显的新生儿肝内胆汁淤积证据，扩大了citrin缺乏的临床谱。该病例强调了对citrin缺乏引起的新生儿肝内胆汁淤积患儿持续进行饮食控制和生长监测的重要性，并确定了一种导致生长发育不良的新的代谢实体。
