Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty,European Journal of Endocrinology

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Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty
European Journal of Endocrinology ( IF 5.8 ) Pub Date : 2021-11-01 , DOI: 10.1530/eje-21-0387
Tansit Saengkaew _{1,

2} , Heena R Patel _{1,

3} , Kausik Banerjee ₄ , Gary Butler _{5,

6} , Mehul T Dattani _{5,

6,

7} , Michael McGuigan ₈ , Helen L Storr _{1,

9} , Ruben H Willemsen ₉ , Leo Dunkel _{1,

9} , Sasha R Howard _{1,

9}

Affiliation

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Endocrinology Unit, Department of Paediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.
Department of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norfolk, UK.
Department of Paediatrics, Barking, Havering and Redbridge University Hospitals NHS Trust, London, UK.
Department of Paediatric and Adolescent Endocrinology, University College London Hospital NHS Foundation Trust, London, UK.
UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Department of Paediatrics, Countess of Chester NHS Foundation Trust, Chester, UK.
Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK.

Context

Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective

To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients.

Design

Retrospective study.

Methods

Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results

Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion

This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

中文翻译：

基因评估支持青春期延迟青少年患者的鉴别诊断

语境

青春期延迟可能是特发性低促性腺激素性性腺功能减退症 (IHH) 和自限性青春期延迟 (SLDP) 的临床表现。区分这些疾病是青少年常见但重要的诊断挑战。

客观的

评估基因组检测是否有助于临床鉴别诊断，并允许对青春期延迟患者进行准确及时的管理。

设计

回顾性研究。

方法

包括在英国儿科服务机构就诊的青春期延迟患者，随访至最终诊断。使用先前报道的导致 IHH 或 SLDP 识别很少预测的有害变体的虚拟基因组分析全外显子组测序。通过计算机预测工具验证了有害变体。分析临床与基因型诊断的相关性。

结果

纳入了 46 名患者，其中 54% 最终临床诊断为 SLDP，46% 为 IHH。只有三名患者出现 IHH 的红旗迹象。在 33% 的队列中发现了 12 个基因中的 15 个预测有害变异，其中大多数以杂合方式遗传。发现最终临床诊断和基因型诊断之间存在公平的相关性。小组测试能够确认青春期延迟患者的 IHH 诊断。遗传分析确定了三名先前被诊断为 SLDP 的 IHH 患者。