Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication

2014-05-28 13:36:29

American Journal of Medical Genetics Part A; 2014 May 28; DOI: 10.1002/ajmg.a.36605

Isabel Filges, Steven Sparagana, Michael Sargent, Kathryn Selby, Kamilla Schlade-Bartusiak, Gregg T. Lueder, Amy Robichaux-Viehoever, Bradley L. Schlaggar, Joshua S. Shimony and Marwan Shinawi


The phenotype of recurrent -600 kb microdeletion and microduplication on proximal 16p11.2 is characterized by a spectrum of neurodevelopmental impairments including developmental delay and intellectual disability, epilepsy, autism and psychiatric disorders which are all subject to incomplete penetrance and variable expressivity. A variety of brain MRI abnormalities were reported in patients with 16p11.2 rearrangements, but no systematic correlation has been studied among patients with similar brain anomalies, their neurodevelopmental and clinical phenotypes. We present three patients with the proximal 16p11.2 microduplication exhibiting significant developmental delay, anxiety disorder and other variable clinical features. Our patients have abnormal brain MRI findings of cerebral T2 hyperintense foci (3/3) and ventriculomegaly (2/3). The neuroradiological or neurological findings in two cases prompted an extensive diagnostic work-up. One patient has exhibited neurological regression and progressive vision impairment and was diagnosed with juvenile neuronal ceroid-lipofuscinosis. We compare the clinical course and phenotype of these patients in regard to the clinical significance of the cerebral lesions and the need for MRI surveillance. We conclude that in all three patients the lesions were not progressive, did not show any sign of malignant transformation and could not be correlated to specific clinical features. We discuss potential etiologic mechanisms that may include overexpression of genes within the duplicated region involved in control of cell proliferation and complex molecular mechanisms such as the MAPK/ERK pathway. Systematic studies in larger cohorts are needed to confirm our observation and to establish the prevalence and clinical significance of these neuroanatomical abnormalities in patients with 16p11.2 duplications.


The phenotype of recurrent 600 kb microdeletion and microduplication on 16p11.2 is characterized by a spectrum of neurodevelopmental impairments including developmental delay (DD) and intellectual disability (ID), epilepsy, autism and psychiatric disorders; all are subject to incomplete penetrance and variable
expressivity. The prevalence of either the microdeletion or microduplication has been estimated to be approximately 1% in individuals with autism and/
or developmental delay. Rosenfeld et al. [2010] showed speech delays and behavioral problems to be the predominant features in 32 individuals with 16p11.2 microduplications who were referred for chromosomal microarray analysis because of developmental delay though these features were not as consistent as in individuals with microdeletions. Reciprocal alterations in gene dosage at 16p11.2 result in mirror and contrasting phenotypes. Abnormal head size—macrocephaly in
individuals with 16p11.2 microdeletion and microcephaly in individuals with the reciprocal microduplication—has been reported. More recently, an association of obesity with the deletion and significantly reduced postnatal weight and body mass index (BMI) among duplication carriers have been observed

A wide spectrum of minor and major congenital anomalies has been reported in patients with 16p11.2 genomic rearrangements. However, these anomalies do not appear to have a consistent pattern. They were reported in 50% of patients with duplications. Rosenfeld et al. [2010] found congenital anomalies in 5 out of 32 patients with 16p11.2 microduplication, but clinical information was only complete for 10 patients. Malformations were also reported in 29/101 patients with 16p11.2 microduplications ascertained for ID/DD; 13 of the 29 patients had central nervous system anomalies. However, the precise prevalence of brain anomalies is difficult to assess because of ascertainment bias, as imaging studies were not systematically performed in all carriers of 16p11.2 microduplications. Nevertheless, abnormal central nervous system (CNS) imaging findings reported by now in patients with 16p11.2 microduplications included white matter changes and atrophy and gliosis of thalami, cerebellar anomalies including cysts, hypoplasia and abnormal striations, cortical dysplasia, myelination delay. Until now, no systematic correlation has been made between patients with similar brain anomalies and their neurodevelopmental and physical phenotypes.

In this case series, we describe the neurological course and brain MRI findings in three patients with proximal 16p11.2 microduplication including an unexpected neurological deterioration in one patient who was ultimately diagnosed with neuronal juvenile ceroid-lipofuscinosis (JNCL). We discuss the brain imaging abnormalities including ventriculomegaly and multiple T2 hyperintense lesions and suggest a potential mechanism for their formation. The clinical relevance of the neuroimaging findings is unclear and raises questions regarding the utility of routine brain MRI in the clinical care and surveillance of patients with 16p11.2 rearrangements.

To Access Article, Click Here