Steyn Nicolene, Chale-Matsau Bettina, Abera Aron B, van Biljon Gertruida, Pillay Tahir S
Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
National Health Laboratory Service, Tshwane Academic Division, Pretoria, South Africa.
Afr J Lab Med. 2023 Apr 14;12(1):1998. doi: 10.4102/ajlm.v12i1.1998. eCollection 2023.
Liddle syndrome is an autosomal dominantly inherited disorder usually arising from single mutations of the genes that encode for the alpha, beta and gamma epithelial sodium channel (ENaC) subunits. This leads to refractory hypertension, hypokalaemia, metabolic alkalosis, hyporeninaemia and hypoaldosteronism, through over-activation of the ENaC.
We describe a 5-day old neonate who presented with severe hypernatraemic dehydration requiring admission to Steve Biko Academic Hospital in South Africa in 2012. Further evaluation revealed features in keeping with Liddle syndrome. Two compound heterozygous mutations located at different subunits encoding the ENaC were detected following genetic sequencing done in 2020. The severe clinical phenotype observed here could be attributed to the synergistic effect of these known pathological mutations, but may also indicate that one of the other variants detected has hitherto undocumented pathological effects.
This child's treatment course was complicated by poor adherence to therapy, requiring numerous admissions over the years. Adequate blood pressure control was achieved only after the addition of amiloride at the end of 2018, which raised the suspicion of an ENaC abnormality.
To our knowledge, this is the first Liddle syndrome case where a combined effect from mutations resulted in severe disease. This highlights the importance of early recognition and management of this highly treatable genetic disease to prevent the grave sequelae associated with long-standing hypertension. Whole exome sequencing may assist in the detection of known mutations, but may also unveil new potentially pathological variants.
This study highlights the importance of developing a high index of suspicion of tubulopathy such as Liddle syndrome for any child presenting with persistent hypertension associated with hypokalaemic metabolic alkalosis.
利德尔综合征是一种常染色体显性遗传疾病，通常由编码α、β和γ上皮钠通道（ENaC）亚基的基因突变引起。这会导致ENaC过度激活，进而引发难治性高血压、低钾血症、代谢性碱中毒、低肾素血症和低醛固酮血症。
我们描述了一名5天大的新生儿，于2012年因严重高钠血症脱水被收治入南非史蒂夫·比科学术医院。进一步评估发现其特征符合利德尔综合征。2020年进行基因测序后，检测到位于编码ENaC不同亚基上的两个复合杂合突变。此处观察到的严重临床表型可能归因于这些已知病理突变的协同作用，但也可能表明检测到的其他变异之一具有迄今未记录的病理效应。
该患儿的治疗过程因治疗依从性差而复杂化，多年来需要多次入院。直到2018年底加用氨氯吡咪后才实现了充分的血压控制，这引发了对ENaC异常的怀疑。
据我们所知，这是首例因突变联合效应导致严重疾病的利德尔综合征病例。这凸显了早期识别和管理这种高度可治疗的遗传疾病以预防与长期高血压相关的严重后遗症的重要性。全外显子组测序可能有助于检测已知突变，但也可能揭示新的潜在病理变异。
本研究强调了对于任何出现与低钾血症性代谢性碱中毒相关的持续性高血压的儿童，提高对肾小管疾病（如利德尔综合征）怀疑指数的重要性。
