Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations

Highlights

• ANKRD11 aberrations have been associated to KBG syndrome.

• Brain structural abnormalities are rarely reported in this syndrome.

• We describe two novel mutations in ANKRD11.

• Uncinate fascicles asymmetry and frontal sulcation anomalies were found in all cases.

• All patients had an IQ > 70, but they showed cognitive and socioemotional deficits.

Abstract

KBG syndrome is characterized by dental, craniofacial and skeletal anomalies, short stature and global developmental delay or intellectual disability. It is caused by microdeletions or truncating mutations of ANKRD11. We report four unrelated probands with this syndrome due to de novo ANKRD11 aberrations that may contribute to a better understanding of the genetics and pathophysiology of this autosomal dominant syndrome. Clinical, cognitive and MRI assessments were performed. Three of the patients showed normal intellectual functioning, whereas the fourth had a borderline level of intellectual functioning. However, all of them showed deficits in various cognitive and socioemotional processes such as attention, executive functions, empathy or pragmatic language. Moreover, all probands displayed marked asymmetry of the uncinate fascicles and an abnormal gyrification pattern in the left frontal lobe. Thus, structural neuroimaging anomalies seem to have been overlooked in this syndrome. Disturbed frontal gyrification and/or lower structural integrity of the uncinate fascisulus might be unrecognized neuroimaging features of KBG syndrome caused by ANKRD11 aberrations. Present results also point out that this syndrome is not necessarily associated with global developmental delay and intellectual disability, but it can be related to other neurodevelopmental disorders or subclinical levels of attention-deficit hyperactivity disorder, autism, communication disorders or specific learning disabilities.

Introduction

The KBG syndrome (MIM# 611192) is characterized by macrodontia of the upper central incisors, characteristic facial features, short stature, skeletal anomalies and developmental delay/intellectual disability [[1], [2], [3], [4], [5], [6], [7], [8]]. This syndrome is caused by either loss-of-function mutations in the Ankyrin repeat domain-containing protein 11 (ANKRD11) gene or microdeletions in chromosome 16q24.3 including this gene [9,10].

Although cognitive skills are variable in patients with KBG syndrome, intellectual disability (ID) has been described in more than 95% of affected cases. Moreover, autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are observed in 19 and 64% of cases, respectively [2,7].

Structural brain malformations are infrequent and unspecific in this syndrome, although its real incidence is unknown because brain MRI has not been performed in all cases or in large cohorts [3]. Overall 50–70% of cases were reported to have normal standard brain MRI [4,10], although the frequency of normal results drops to 20% in some cohorts [2]. Several infratentorial abnormalities have been described (enlarged cysterna magna, Chiari malformations, and hypoplasia of the cerebellar vermis or hemispheres); periventricular heterotopia, dysgenesis of the corpus callosum, enlarged ventricles, and arachnoid cysts have also been reported [2,[10], [11], [12], [13]]. However, most of these reported anomalies have been described as incidental findings on brain imaging in healthy young population [14,15] and the detection of these malformations might be conditioned by the expectations of the clinician and the radiologist [16]. Moreover, it should be noted that these incidental abnormalities in the brain images do not seem to explain the intellectual and cognitive deficits shown by patients with KBG syndrome.

Here, we describe four cases with de novo ANKRD11 aberrations. In all individuals standard brain imaging revealed sulcation anomalies in left frontal lobes without evidence of macroscopic polymicrogiria, and Diffusion Tensor Imaging (DTI) tractography showed hypoplastic left uncinate fascicles. All patients had an intellectual quotient (IQ) within normal limits, but they showed deficits in several cognitive and socioemotional functions.