P-001 | Prenatal Description and Post-Mortem Characterization of a Progressive, Massive Cerebral Tumor in an Early Deceased Newborn: Evidence Supporting a Diagnosis of BRCA2-Related Fanconi Anemia

Agnese Feresin¹ Agnese Feresin^1,2, Nicolas Bourgon^3,4, Elisa Zanelli⁵, Pascale Sonigo⁵, David Grevent⁵, Philippe Roth³, Lise Larcher⁶, Jean Soulier⁶, Silvana Kalakech⁷, FerechteRazavi², Pascale Varlet⁷, Bettina Bessières²

¹University of Study of Trieste, Trieste, Italy; ²Service de MédecineGénomiquedes Maladies Rares, UF MP5 (MédecinePréimplantatoire, Prénatale, Périnataleurgent, Pathologiefœtaleet Placentaire) HôpitalNecker-Enfants Malades, Paris, France; ³Service d'Obstétrique-MaternitéChirurgie, Médecineet ImageriefœtalesHôpitalNecker Enfants Malades, Paris, France; ⁴INSERM UMR 894 – Génétiqueet développementdu cortex cerebral InstitutImagine, Paris, France; ⁵RadiologiePédiatrieHôpitalNecker-Enfants Malades, Paris, France; ⁶Institutde Recherche Saint-Louis (IRSL) -Université de Paris-CitéHôpitalSaint-Louis, Paris, France; ⁷Service NeuropathologiePôleNeuro-Sainte-Anne, Paris, France

Objectives: Describe prenatal and post-mortem phenotype of an early deceased newborn with brain tumor; illustrate the diagnostic process; strength the importance of a final diagnosis.

Methods: Family history collection; prenatal (US, MRI) and post-mortem imaging (CT), external examination, neuropathological analysis (macroscopy, histology, specific markers); molecular analysis (arrayCGH, flow cytometry-based Mitomycin C sensitivity test in fibroblasts, NGS gene panel).

Results: This is the second, spontaneous pregnancy of an apparently healthy and unrelated couple from Northern Africa, with family histories of breast cancers.

Second-trimester US highlighted a severe growth restriction with ventriculomegaly, MRI contributed to describe a heterogeneous brain tumor associated with progressive hydrocephalus. Chromosomal anomalies and cytomegalovirus infection were excluded. Spontaneous, premature birth occurred at 34 + 1 weeks of gestation and the newborn died at 15 min of life. The female newborn was pale, showed growth delay with relative macrocrania and pre-axial duplication of the left thumb. Total-body CT scan documented also hemi-vertebrae, hepatomegaly with possible lesions, and splenomegaly.

Brain macroscopic examination described a solid mass measuring 9.5 × 7.0 centimeters, displacing cerebral and cerebellar tissue, showing a heterogeneous aspect with necrotic-hemorrhagic component at section. The histologic analysis concluded for an embryonal tumor with multilayered rosettes surrounded by inflammatory reaction. Diffuse erythroblastosis was possibly related to anemia.

Flow cytometry-based mitomycin C sensitivity performed on cutaneous fibroblasts showed hypersensitivity without abnormality on the FANCD2-monoubiquitination assays, suggesting Fanconi anemia (FA) of the “downstream” subgroup. Gene panel sequencing found a homozygous, pathogenic BRCA2 variant (p.K437Ifs*22) in tumoral and non-tumoral tissues. Copy number analysis of the tumor evidenced multiple gains and losses in accordance with the genomic signature of repair deficiency.

Conclusions: We report a diagnosis of BRCA2/FANCD1 FA in a neonate with brain tumor. In front of antenatal/neonatal tumor, phenotypical description will distinguish isolated cases from syndromic associations. Family history and clinical characterization are crucial to guide complementary analysis, deliver appropriate genetic counseling and preventive cancer strategies to the family.

中文翻译：

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ISPD 第 27 届国际产前诊断与治疗会议海报摘要，英国爱丁堡，2023 年 6 月 19-21 日

P-001 | 早期死亡新生儿进行性巨大脑肿瘤的产前描述和尸检特征：支持 BRCA2 相关范可尼贫血诊断的证据

艾格尼丝·费雷辛¹艾格尼丝·费雷辛^1,2 , 尼古拉斯·布尔贡^3,4 , Elisa Zanelli ⁵ , 帕斯卡尔·索尼戈⁵ , 大卫·格雷文特⁵ , 菲利普·罗斯³ ,莉斯·拉彻⁶ , 让·苏利埃⁶ , 西尔瓦娜·卡拉克什⁷ , FerechteRazavi ² , 帕斯卡尔·瓦莱⁷ ,贝蒂娜·贝西埃²

^{1 的}里雅斯特研究大学，意大利的里雅斯特； ² Service de MédecineGénomiquedes Maladies Rares，UF MP5（MédecinePréimplantatoire、Prénatale、Périnataleurgent、Pathologiefœtaleet Placentaire）HôpitalNecker-Enfants Malades，巴黎，法国； ³ Service d'Obstétrique-MaternitéChirurgie，Médecineet ImageriefœtalesHôpitalNecker Enfants Malades，法国巴黎； ⁴ INSERM UMR 894 – 大脑皮层发育基因研究所，法国巴黎； ^{5RadiologiePédiatrieHôpitalNecker} -Enfants Malades，法国巴黎； ⁶圣路易斯研究所 (IRSL) - 巴黎大学圣路易斯医院，法国巴黎； ⁷神经病理学服务中心 PôleNeuro-Sainte-Anne，法国巴黎

目的：描述患有脑肿瘤的早期死亡新生儿的产前和死后表型；说明诊断过程；强调最终诊断的重要性。

方法：收集家族史；产前（US、MRI）和死后成像（CT）、外部检查、神经病理学分析（肉眼观察、组织学、特异性标记物）；分子分析（arrayCGH、基于流式细胞术的成纤维细胞丝裂霉素 C 敏感性测试、NGS 基因组）。

结果：这是一对来自北非、表面健康、无血缘关系、有乳腺癌家族史的夫妇第二次自然怀孕。

中期妊娠美国强调了脑室扩张的严重生长限制，MRI 有助于描述与进行性脑积水相关的异质性脑肿瘤。排除染色体异常和巨细胞病毒感染。妊娠 34+1 周时发生自然早产，新生儿在出生 15 分钟后死亡。女新生儿面色苍白，生长迟缓，伴有相对大颅骨和左拇指轴前重复。全身 CT 扫描还记录了半椎骨、可能存在病变的肝肿大和脾肿大。

脑部宏观检查显示有一个 9.5 × 7.0 厘米的固体肿块，取代了大脑和小脑组织，切片显示出异质性，伴有坏死出血成分。组织学分析得出结论，胚胎肿瘤具有被炎症反应包围的多层玫瑰花结。弥漫性成红细胞增多症可能与贫血有关。

基于流式细胞术的皮肤成纤维细胞丝裂霉素 C 敏感性显示，FANCD2 单泛素化检测显示超敏反应，无异常，提示“下游”亚组存在范可尼贫血 (FA)。基因组测序在肿瘤和非肿瘤组织中发现了纯合致病性BRCA2变异 (p.K437Ifs*22)。肿瘤的拷贝数分析证明了根据修复缺陷的基因组特征的多种增益和损失。

结论：我们报告了一名脑肿瘤新生儿的 BRCA2/FANCD1 FA 诊断。在产前/新生儿肿瘤面前，表型描述将区分孤立病例和综合征关联。家族史和临床特征对于指导补充分析、向家族提供适当的遗传咨询和预防癌症策略至关重要。