Abstract：
BACKGROUND: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.
METHODS: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.
RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.
CONCLUSIONS: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.
METHODS: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.
RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.
CONCLUSIONS: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.
摘要：
背景：Tonne-Kalscheuer综合征（TOKAS）是由RLIM变异引起的隐性X连锁多发性先天性异常疾病。在报告的41名患者中，仅描述了7例产前病例。
方法：在一个家庭中通过外显子组分析对TOKAS进行产前诊断后，由于五个男性胎儿的多种先天性异常，该家庭随访了35年以上，呼吁合作，导致11个以前未发表的病例。
结果：我们介绍了一个TOKAS产前队列，描述了6个法国家庭的11个新病例。我们报告了高频率的膈疝（11个中的9个），性发育差异(11个中的10个)和各种内脏畸形。我们报告了一些反复出现的畸形特征，还有桥小脑发育不全，耳前皮肤标签和嗅球异常以前在文献中没有报道。尽管尚未出现明确的基因型-表型相关性，我们显示复发性p。（Arg611Cys）变异占胎儿TOKAS病例的66％。我们还报告了RLIM中的两种新的可能致病变异，在两个先前已知的突变热点之外。
结论：总体而言，我们介绍了TOKAS的第一个胎儿队列，描述使其在胎儿病理学检查中成为可识别综合征的临床特征，并扩展这种罕见疾病的表型谱和已知基因型。
方法：在一个家庭中通过外显子组分析对TOKAS进行产前诊断后，由于五个男性胎儿的多种先天性异常，该家庭随访了35年以上，呼吁合作，导致11个以前未发表的病例。
结果：我们介绍了一个TOKAS产前队列，描述了6个法国家庭的11个新病例。我们报告了高频率的膈疝（11个中的9个），性发育差异(11个中的10个)和各种内脏畸形。我们报告了一些反复出现的畸形特征，还有桥小脑发育不全，耳前皮肤标签和嗅球异常以前在文献中没有报道。尽管尚未出现明确的基因型-表型相关性，我们显示复发性p。（Arg611Cys）变异占胎儿TOKAS病例的66％。我们还报告了RLIM中的两种新的可能致病变异，在两个先前已知的突变热点之外。
结论：总体而言，我们介绍了TOKAS的第一个胎儿队列，描述使其在胎儿病理学检查中成为可识别综合征的临床特征，并扩展这种罕见疾病的表型谱和已知基因型。
