Joustra Sjoerd D, Isik Emregul, Wit Jan M, Catli Gonul, Anik Ahmet, Haliloglu Belma, Kandemir Nurgun, Ozsu Elif, Hendriks Yvonne M C, de Bruin Christiaan, Kant Sarina G, Campos-Barros Angel, Challis Rachel C, Parry David, Harley Margaret E, Jackson Andrew, Losekoot Monique, van Duyvenvoorde Hermine A
Department of Paediatrics, Division of Pediatric Endocrinology, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.
Department of Paediatrics, Ankara Bilkent City Hospital, Ankara, Turkey.
Horm Res Paediatr. 2024 Jun 5:1-11. doi: 10.1159/000539696.
The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented.
This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c).
In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively.
Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.
对身材矮小儿童进行评估时，基因分析的诊断价值取决于相关临床特征，但父母近亲结婚的额外影响尚未得到充分记录。
本观察性病例系列收集了来自34个近亲家庭的42名身材矮小儿童（纳入标准：身材矮小且父母近亲结婚），由六个儿科内分泌转诊中心完成。18例患者（12个家庭，第1组）的临床特征提示生长激素（GH）-胰岛素样生长因子I（IGF-I）轴存在特定基因缺陷，采用候选基因法。其他患者（第2组）则采用无假设方法（基因panel、微阵列分析和全外显子组测序），并进一步细分为11例严重身材矮小（身高<-3.5标准差评分[SDS]）且小头畸形（头围<-3.0 SDS）的患者（第2a组）、10例综合征性身材矮小患者（第2b组）和3例非特异性孤立性GH缺乏患者（第2c组）。
第1组的所有12个家庭中，在GHR、IGFALS、GH1和STAT5B中鉴定出（可能）致病变异。第2a组的12个家庭中有9个检测到PCNT、SMARCAL1、SRCAP、WDR4和GHSR中的变异。第2b组的9个家庭中有5个在TTC37、SCUBE3、NSD2、RABGAP1和17p13.3微缺失中发现变异。第2c组未发现遗传病因。分别在21例、1例和4例患者中发现纯合、复合杂合和杂合变异。
对近亲父母所生身材矮小儿童进行基因检测具有较高的诊断价值，尤其是在严重GH缺乏或不敏感、小头畸形和综合征性身材矮小的病例中。
