Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val
Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val
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DOI：
10.1002/ajmg.a.35296
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发表时间：
2012-05-01
影响因子：
2
通讯作者：
Kerr, Bronwyn
中科院分区：
文献类型：
--
作者：
Burkitt-Wright, Emma M. M.;Bradley, Lisa;Kerr, Bronwyn
HRAS基因的新杂合突变导致Costello综合征(CS)，这种疾病在婴儿和儿童早期因心脏、呼吸系统和肌肉并发症而具有高死亡率和发病率。预测p.Gly12Val、p.Gly12Asp和p.Gly12Cys替换的HRAS突变与严重、致命性CS相关。我们报告了在我们的临床分子基因检测服务中发现的具有预测HRAS p.Gly12Val突变的患者的分子、临床和病理结果。在四名患者中发现了这种突变。值得注意的是，有三个是影响编码核苷酸35和36的缺失/插入突变。所有患者在出生后6周内死亡，进一步证明P.Gly12Val突变预示着非常糟糕的预后。出生体重高、羊水过多(和早产)、心肌肥大、呼吸窘迫、肌肉无力和出生后生长障碍。畸形是轻微的或非特异性的，伴有水肿、面部特征粗糙、额头突出、鼻梁凹陷、鼻孔前倾和耳朵低垂。上肢近端短缩，小的钟形胸部，距腿，以及手腕的固定性屈曲畸形。新生儿房性心律失常，高度提示CS，也存在于两名患者。1例为先天性肺泡发育不良，另1例为妊娠36周后出生的支气管肺发育不良。一个迅速致命的病程，以及在需要重症监护的新生儿中识别微小的畸形的困难，表明这种情况仍然没有得到充分的认识，应该进入有一系列临床问题的重症婴儿的鉴别诊断，包括心肌肥大和肺发育障碍。临床治疗应该了解这种情况的不良预后。(C)2012年威利期刊公司。
De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. (c) 2012 Wiley Periodicals, Inc.