van Dijk Fleur S, Mancini Grazia M S, Maugeri Alessandra, Cobben Jan M
North West Thames Regional Genetics Service, Ehlers-Danlos Syndrome National Diagnostic Service London, North West Health Care NHS Trust, Harrow, Middlesex, UK; Department of Clinical Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Eur J Med Genet. 2017 Oct;60(10):536-540. doi: 10.1016/j.ejmg.2017.07.011. Epub 2017 Jul 27.
We report two children with Ehlers Danlos, kyphoscoliotic type confirmed by Lysyl Hydroxylase 1 deficiency due to bi-allelic PLOD1 mutations (kEDS-PLOD1) who were initially thought to have either a diagnosis of classical EDS (cEDS) or a neuromuscular disorder due to absence of (congenital) scoliosis. As the two patients reported here illustrate, patients with kEDS-PLOD1 do not always have a kyphoscoliosis present at birth or in the first year of life, neither do they necessarily develop kyphoscoliosis later in infancy. Using the past criteria for kEDS there was considerable overlap with the clinical diagnostic criteria for EDS classical type. In the patients reported here without (kypho) scoliosis this has delayed the diagnosis, which is unfortunate as the diagnosis of kEDS-PLOD1 results in a different recurrence risk and has management consequences. Interestingly, the new criteria for kEDS would not have prevented this diagnostic delay as congenital or early onset kyphoscoliosis (progressive or non-progressive) is deemed obligatory for the diagnosis of kEDS. Being aware of the limitations of clinical diagnostic criteria, we recommend that (i) in patients without a positive family history nor identified COL5A1/2 mutations, lysyl hydroxylase deficiency or biallelic PLOD1 mutations should be excluded before the diagnosis classical EDS can be made and (ii) PLOD1 and COL5A1/2 should be included in the same Next Generation Sequencing (NGS) gene panel.
我们报告了两名患有埃勒斯-当洛综合征（Ehlers Danlos）脊柱后侧凸型（kyphoscoliotic type）的儿童，该疾病由双等位基因PLOD1突变导致赖氨酰羟化酶1缺乏所证实（kEDS-PLOD1）。他们最初被认为患有经典型埃勒斯-当洛综合征（cEDS）或因无（先天性）脊柱侧凸而被诊断为神经肌肉疾病。正如本文报道的两名患者所示，kEDS-PLOD1患者并非总是在出生时或生命的第一年就出现脊柱后侧凸，也不一定在婴儿期后期发展为脊柱后侧凸。按照过去kEDS的标准，与经典型埃勒斯-当洛综合征的临床诊断标准有相当大的重叠。在本文报道的无（脊柱后凸）脊柱侧凸的患者中，这导致了诊断延迟，这很不幸，因为kEDS-PLOD1的诊断会导致不同的复发风险并产生管理方面的影响。有趣的是，kEDS的新标准并不能避免这种诊断延迟，因为先天性或早发性脊柱后侧凸（进行性或非进行性）被认为是kEDS诊断的必要条件。鉴于临床诊断标准的局限性，我们建议：（i）在没有阳性家族史且未鉴定出COL5A1/2突变的患者中，在做出经典型埃勒斯-当洛综合征的诊断之前，应排除赖氨酰羟化酶缺乏或双等位基因PLOD1突变；（ii）PLOD1和COL5A1/2应包含在同一二代测序（NGS）基因面板中。
