AUTHOR=Roberti Domenico , Conforti Renata , Giugliano Teresa , Brogna Barbara , Tartaglione Immacolata , Casale Maddalena , Piluso Giulio , Perrotta Silverio 

TITLE=A Novel 12q13.2-q13.3 Microdeletion Syndrome With Combined Features of Diamond Blackfan Anemia, Pierre Robin Sequence and Klippel Feil Deformity

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00549

DOI=10.3389/fgene.2018.00549

ISSN=1664-8021

ABSTRACT=<p>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.</p><p>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.</p><p>Klippel Feil (KF) syndrome is a complex of both osseous and visceral anomalies, characterized mainly by congenital development defects of the cervical spine.</p><p>We describe the case of a 22-years-old woman affected by DBA, carrying a <italic>de novo</italic> deletion about 500 Kb-long at 12q13.2-q13.3 that included <italic>RPS26</italic> 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 (AOA), 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.</p><p>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 (<italic>MMP19</italic>), in cell cycle regulation (<italic>CDK2)</italic>, vesicular trafficking (<italic>RAB5B)</italic>, in ribonucleoprotein complexes formation (<italic>ZC3H10</italic>) and muscles function (<italic>MYL6</italic> and <italic>MYL6B</italic>) 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 (<italic>RPS26, PA2G4</italic> and <italic>RPL41)</italic>, and it confirms the association among <italic>SLC39A5</italic> functional disruption and severe myopia.</p><p>This report highlights the need for a careful genetic evaluation and a detailed phenotype-genotype correlation in each complex malformative syndrome.</p>