A Novel 12q13.2-q13.3 Microdeletion Syndrome With Combined Features of Diamond Blackfan Anemia, Pierre Robin Sequence and Klippel Feil Deformity
A Novel 12q13.2-q13.3 Microdeletion Syndrome With Combined Features of Diamond Blackfan Anemia, Pierre Robin Sequence and Klippel Feil Deformity
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DOI：
10.3389/fgene.2018.00549
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发表时间：
2018-11-19
影响因子：
3.7
通讯作者：
Perrotta, Silverio
中科院分区：
文献类型：
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作者：
Roberti, Domenico;Conforti, Renata;Perrotta, Silverio
钻石-布莱克凡贫血（DBA）是一种罕见的先天性红系发育不全，具有高度异质性的遗传背景，它通常发生在婴儿期。大约30-40%的患者有其他相关的先天性异常，特别是面部异常，如腭裂，是约10%的DBA临床表现的一部分。Klippel费勒（KF）综合征是一种复杂的骨骼和内脏异常，其主要特征是颈椎先天性发育缺陷。我们描述了一例22岁女性DBA，在12q13.2-q13.3携带约500 kb长的从头缺失，包括RPS 26和至少25个其他侧翼基因。患者因PRS出现颅面异常，并患有KF畸形（II型）。颅颈交界部（CCJ）的计算机断层扫描研究显示了严重的骨畸形和先天性异常，如寰枕同化（AIDA）、弓状孔和枕髁增生。枕骨大孔严重缩小。寰枢椎不稳（AAI）与寰枕融合、先天性椎体融合和枕髁骨质增生有关。CT和磁共振成像（MRI）检查排除了颅底内陷和扁平底畸形。此外，颞骨CT研究显示外耳道异常，乳突骨化不全，慢性中耳炎和面神经骨道异常。所述表型可能与影响患者的特殊缺失有关，突出了参与细胞外基质分解（MMP 19），细胞周期调节（CDK 2），囊泡运输（RAB 5 B），核糖核蛋白复合物形成（ZC 3 H 10）和肌肉功能（MYL 6和MYL 6 B）可能与骨发育障碍有关。此外，它指出，多个相关的核糖体缺陷可能在DBA相关表型中发挥作用，考虑到在索引病例中同时缺失其中三个（RPS 26、PA 2G 4和RPL 41），并证实了SLC 39 A5功能破坏与严重近视之间的关联。该报告强调了仔细的遗传评估和详细的表型的必要性，各复杂畸形综合征的基因型相关性。
Diamond-Blackfan anemia (DBA) is a rare congenital erythroid aplasia with a highly heterogeneous genetic background; it usually occurs in infancy. Approximately 30-40% of patients have other associated congenital anomalies; in particular, facial anomalies, such as cleft palate, are part of about 10% of the DBA clinical presentations.Pierre Robin sequence (PRS) is a heterogeneous condition, defined by the presence of the triad of glossoptosis, micrognathia and cleft palate; it occurs in 1/8500 to 1/14,000 births.Klippel Feil (KF) syndrome is a complex of both osseous and visceral anomalies, characterized mainly by congenital development defects of the cervical spine.We describe the case of a 22-years-old woman affected by DBA, carrying a de novo deletion about 500 Kb-long at 12q13.2-q13.3 that included RPS26 and, at least, others 25 flanking genes. The patient showed craniofacial anomalies due to PRS and suffered for KF deformities (type II). Computed Tomography study of cranio-cervical junction (CCJ) drew out severe bone malformations and congenital anomalies as atlanto-occipital assimilation (AIDA), arcuate foramen and occipito-condylar hyperplasia. Foramen magnum was severely reduced. Atlanto-axial instability (AAI) was linked to atlanto-occipital assimilation, congenital vertebral fusion and occipito-condyle bone hyperplasia. Basilar invagination and platybasia were ruled out on CT and Magnetic Resonance Imaging (MRI) studies. Furthermore, the temporal Bone CT study showed anomalies of external auditory canals, absent mastoid pneumatization, chronic middle ear otitis and abnormal course of the facial nerve bones canal.The described phenotype might be related to the peculiar deletion affecting the patient, highlighting that genes involved in the in the breakdown of extracellular matrix (MMP19), in cell cycle regulation (CDK2), vesicular trafficking (RAB5B), in ribonucleoprotein complexes formation (ZC3H10) and muscles function (MYL6 and MYL6B) could be potentially related to bone-developmental disorders. Moreover, it points out that multiple associated ribosomal deficits might play a role in DBA-related phenotypes, considering the simultaneous deletion of three of them in the index case (RPS26, PA2G4 and RPL41), and it confirms the association among SLC39A5 functional disruption and severe myopia.This report highlights the need for a careful genetic evaluation and a detailed phenotype-genotype correlation in each complex malformative syndrome.