Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Distal deletion at 22q11.2 as differential diagnosis in Craniofacial Microsomia: Case report and literature review.

Craniofacial Microsomia (CFM) also known as Oculo-auriculo-vertebral Spectrum (OAVS) or Goldenhar Syndrome, presents wide phenotypic and etiological heterogeneity. It affects mainly the structures originated from the first and second pharyngeal arches. In addition, other major anomalies may also be found, including congenital heart diseases. In this study, we report a patient with distal deletion in the 22q11.2 region and a phenotype which resembles CFM. The proband is a girl, who presented bilateral preauricular tags, left auditory canal stenosis, malar hypoplasia, cleft lip and palate, mild asymmetry of soft tissue in face, congenital heart disease, intestinal atresia, annular pancreas and hydronephrosis. The genomic imbalances investigation by Multiplex Ligation-dependent Probe Amplification (MLPA) and Chromosomal Microarray Analysis (CMA) revealed a distal deletion of 1,048 kb at 22q11.2 encompassing the region from Low Copy Repeats (LCRs) D to E. We did review of the literature and genotype-phenotype correlation. This is the sixth case of distal 22q11.2 deletion resembling CFM and the second encompassing the region between LCRs D to E. All cases share some phenotypic signs, such as preauricular tags, facial asymmetry, cleft lip and palate, and congenital heart diseases. Candidate genes in this region have been studied by having an important role in pharyngeal arches developmental and in congenital heart diseases, such as HIC2, YPEL1and MAPK1/ERK2. This case corroborates the phenotypic similarity between 22q11.2 distal deletion and CFM/OAVS. It also contributes to genotype-phenotype correlation and reinforces that candidate genes for CFM, in the 22q11.2 region, might be located between LCRs D and E.