Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations
Graphical abstract
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.
Section snippets
Identification of cases with aberrations in the ANKRD11 gene
We reviewed 505 cases of trio exome sequencing performed in our department since 2014, searching for ANKRD11 mutations. All studies were performed on patients with neurodevelopmental disorders of probable genetic origin. We identified three unrelated cases with truncating mutations in ANKRD11. After this first review, we checked the cases analyzed through CGH arrays, looking for other patients with intragenic deletions of the ANKRD11 gene; we identified and included in this series a fourth Case
Clinical features of the patients
Case 1 The patient is an 11-year-old male, the first child of healthy parents of Spanish origin. There was no relevant family history.
Physical examination revealed a weight of 36 kg (50th centile), height of 132 cm (<3rd centile), and OFC of 52.5 cm (50th centile). Some dysmorphic features were observed: round face, coarse hair, low bitemporal and posterior hairlines, hypertelorism, almond shaped eyes, anteverted nostrils and macrodontia of upper central incisors, and brachydactyly. (Fig. 1A–C).
The
Discussion
We report four cases with KBG syndrome, three of them with ANKRD11 aberrations not previously described. Facial dysmorphism in all cases were similar to others in the literature [[1], [2], [3], [4],9,10].
Three of the patients showed normal intellectual functioning (full-scale IQ within the normal range), whereas the fourth had a borderline level of intellectual functioning (full-scale IQ = 73). However, deficits in attention, executive funtions, language (including pragmatic) and socioemotional
Statement of Ethics
This study complied with the guidelines for human studies and was conducted in accordance with the World Medical Association Declaration of Helsinki. Written consents were obtained from two families to publish patients’ photographs.
Funding sources
This work was supported by the Spanish Ministerio de Economía y Competitividad, MINECO [grant number PSI2017-84922-R], and Comunidad de Madrid [grant number SI1/PJI/2019–00061].
Author contributions
M. Jiménez: acquisition and analysis of MRI images. D. Martín, AL Fernández-Perrone, A. Jiménez, P. Tirado & B. Calleja: study concept and design. S. López-Martín & J. Albert: neuropsychological assessements and study supervision. S. Álvarez: acquisition and analysis of genetic data. A. Fernández-Jaén: study concept and design, study supervision, and critical revision of the manuscript for intellectual content.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Declaration of competing interest
The authors have no conflict of interest to declare.
Acknowledgement
We thank both families for their participation and helpful cooperation in this study.
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