A Not So Benign Family Pedigree With Hereditary Chorea: A Broader Phenotypic Expression or Additional Picture?

Abstract

NKX2-1 mutations have been usually associated with a non-progressive neurological disease. Recent reports revealed a vast variability regarding its clinical expressivity. Aim of this work was widening the Benign Hereditary Chorea neurological, cognitive and behavioral phenotype through the description of a child and her family pedigree. Molecular analysis focused on NKX2-1 gene revealed a novel frameshift mutation in the three-generation members described. Cognitive scales detected a relevant developmental delay, and the clinical observation and Autism Diagnostic Observation Schedule -2 administration allowed the diagnosis of autism spectrum disorder in the proband. Microarray testing, further executed to exclude a double hit contextually provoking the complex neurodevelopmental disorder, revealed the 22q11.2 Duplication Syndrome. This paper may contribute to enlarge Benign Hereditary Chorea variable expressivity and, together with other studies reported in the literature, underlines the need to reconsider the term “benign,” verifying the opportunity of more a complex diagnosis.

Using Genomic Resources for Linkage Analysis in Peromyscus with an Application for Characterizing Dominant Spot

“…Mutations in NKX2-1 cause benign hereditary chorea and have recently been associated with autism (36). Common genetic variations in EBF1 have also been associated with premature birth and autism (37). Functional experiments are necessary to determine the potential impact of this and other non-coding polymorphisms on ASH1L transcription.…”

Using genomic resources for linkage analysis in Peromyscus with an application for characterizing Dominant Spot

“…We show that non-coding polymorphisms change predicted transcription factor binding sites for NKX2-1 and EBF1 in the ASH1L CNS. Mutations in NKX2-1 cause benign hereditary chorea and have recently been associated with autism [44]. Nkx2-1 is expressed in the medial ganglionic eminence (MGE) and is critical for the production of inhibitory gamma amino butyric acid (GABA)eric cortical interneurons [45].…”

Diagnostic Uncertainties: Chorea

“…153,154 Given this expansion, as well as the revelation that the disorder did not always follow such a benign course, the name brain-lung-thyroid syndrome was proposed and has gained some traction in the neurology community. 151,153,154 ADCY-5 Although TITF-1 mutations were found to be a common cause of BHC, they were not universal to patients presenting with a nonprogressive chorea. 155 Several families have now been reported with mutations in ADCY-5.…”

“…152 Once identified, it became clear that BHC mutations comprised one phenotypic presentation of a multisystem disorder with variable presentations. 151 153 154 In addition to chorea, patients were found to have hypotonia, short stature, developmental delay, and other movement disorders including myoclonus, dystonia, and ataxia. Outside of the brain, some patients exhibited respiratory symptoms and congenital hypothyroidism.…”

“…Outside of the brain, some patients exhibited respiratory symptoms and congenital hypothyroidism. 153,154 Given this expansion, as well as the revelation that the disorder did not always follow such a benign course, the Seminars in Neurology Vol. 43 No.…”