Priestley Jessica R C, Alharbi Hana, Callahan Katharine Press, Guzman Herodes, Payan-Walters Irma, Smith Ligia, Ficicioglu Can, Ganetzky Rebecca D, Ahrens-Nicklas Rebecca C
Department of Pediatrics, Division of Human Genetics, Section of Biochemical Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Pediatrics, Pediatric Residency Program, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Int J Neonatal Screen. 2020 Jun;6(2). doi: 10.3390/ijns6020039. Epub 2020 May 16.
Tyrosinemia type 1 (TT1) is an inborn error of tyrosine metabolism with features including liver dysfunction, cirrhosis, and hepatocellular carcinoma; renal dysfunction that may lead to failure to thrive and bone disease; and porphyric crises. Once fatal in most infantile-onset cases, pre-symptomatic diagnosis through newborn screening (NBS) protocols, dietary management, and pharmacotherapy with nitisinone have improved outcomes. Succinylacetone provides a sensitive and specific marker for the detection of TT1 but is not universally utilized in screening protocols for the disease. Here, we report an infant transferred to our facility for evaluation and management of hyperinsulinism who subsequently developed acute-onset liver, respiratory, and renal failure around one month of life. She was found to have TT1 caused by novel pathogenic variant in fumarylacetoacetate hydrolase (c.1014 delC, p.Cys 338 Ter). Her NBS, which utilized tyrosine as a primary marker, had been reported as normal, with a tyrosine level of 151 μmol/L (reference: < 280 μmol/L). Retrospective analysis of dried blood spot samples via tandem mass spectrometry showed detectable succinylacetone ranging 4.65-10.34 μmol/L. To our knowledge, this is the first patient with TT1 whose initial presenting symptom was hyperinsulinemic hypoglycemia. The case highlights the importance of maintaining a high suspicion for metabolic disease in critically ill children, despite normal NBS. We also use the case to advocate for NBS for TT1 using succinylacetone quantitation.
1型酪氨酸血症（TT1）是一种酪氨酸代谢的先天性疾病，其特征包括肝功能障碍、肝硬化和肝细胞癌；可能导致生长发育迟缓及骨骼疾病的肾功能障碍；以及卟啉危象。在大多数婴儿期发病的病例中，TT1曾经是致命的，但通过新生儿筛查（NBS）方案进行症状前诊断、饮食管理以及使用尼替西农进行药物治疗，已改善了预后。琥珀酰丙酮为TT1的检测提供了一种敏感且特异的标志物，但在该疾病的筛查方案中并未普遍使用。在此，我们报告一名因高胰岛素血症转入我院评估和治疗的婴儿，该婴儿在出生后约1个月时随后出现急性肝、呼吸和肾衰竭。她被发现患有由富马酰乙酰乙酸水解酶中的新型致病变异（c.1014 delC，p.Cys 338 Ter）引起的TT1。她的以酪氨酸作为主要标志物的NBS报告为正常，酪氨酸水平为151 μmol/L（参考值：＜280 μmol/L）。通过串联质谱对干血斑样本进行回顾性分析显示可检测到的琥珀酰丙酮范围为4.65 - 10.34 μmol/L。据我们所知，这是首例以高胰岛素低血糖症为初始表现症状的TT1患者。该病例强调了对于重症儿童即使NBS正常也需高度怀疑代谢性疾病的重要性。我们还利用该病例倡导使用琥珀酰丙酮定量法对TT1进行NBS检测。
