Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the <it>NF2 </it>gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient.</p> <p>Case presentation</p> <p>We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing <it>NF2</it>, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including <it>NF2 </it>and <it>MN1 </it>(meningioma 1).</p> <p>Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing <it>NF2 </it>were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed <it>MN1</it>, <it>PITPNB </it>and <it>TTC28</it>. <it>MN1</it>, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (<it>TEL</it>/<it>MN1</it>) in human myeloid leukemias. Interestingly, <it>Mn1</it>-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, <it>Mn1 </it>regulates maturation and function of calvarial osteoblasts and is an upstream regulator of <it>Tbx22</it>, a gene associated with murine and human cleft palate. This suggests that deletion of <it>MN1 </it>in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities.</p> <p>Conclusions</p> <p>Thus, our report describes a <it>NF2</it>-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of <it>MN1 </it>deletion with abnormal craniofacial development and/or cleft palate in humans.</p

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

We thank the Facial Surgery Research Foundation – Saving Faces; Guizhou Department of Education and Guizhou Science and Technology Department

The phenotypic continuum of ATPLA3-related disorders

Background and objectives: ATP1A3 is associated with a broad spectrum of predominantly neurological disorders, that continues to expand beyond the initially defined phenotypes of Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS). This phenotypic variability makes it challenging to assess pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurological disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders (DDD) study with additional cases contributed by collaborators internationally. Detailed clinical data was collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021. Results: Twenty-four individuals with a previously undiagnosed neurological phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurological features were common including microcephaly (7;29%), ataxia (13;54%), dystonia (10;42%) and hypotonia (7;29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. CADD scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within six regions of constraint. Conclusion: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment, as well as evaluating CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone