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Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Brunner HG, van Loon RL, Smeets EE, van Haelst MM, van Haaften G, Nordgren A, Malmgren H, Grigelioniene G, Vermeer S, Louro P, Ramos L, Maal TJ, van Heumen CC, Yntema HG, Carels CE, Kleefstra T - Eur. J. Hum. Genet. (2014)

Bottom Line: Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity.Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent.As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

No MeSH data available.


Related in: MedlinePlus

Two-dimensional clinical photographs and 3D stereophotogrammetry images of patients 5 (a), 1D (b) and 7C (c) are shown which were analysed and compared with composite faces of age- and sex-matched unaffected Dutch controls. Regions in green depict facial structures that are more prominent in the KBG syndrome patients. Red areas are more prominent in controls. In these three patients, the most striking shared facial feature is the bulbous nasal tip, which appears green, and the upturned nose with a broad base (which appears red because this part of the nose is hypoplastic when compared with controls). Patient 5 has a more triangular-shaped face, which is illustrated by the red areas on the lateral side of the face. In contrast, patient 1D has a round face (the lateral sides of the face are green). Patient 7C has a relatively hypoplastic midface and chin compared with controls. The full colour version of this figure is available at European Journal of Human Genetics online.
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fig4: Two-dimensional clinical photographs and 3D stereophotogrammetry images of patients 5 (a), 1D (b) and 7C (c) are shown which were analysed and compared with composite faces of age- and sex-matched unaffected Dutch controls. Regions in green depict facial structures that are more prominent in the KBG syndrome patients. Red areas are more prominent in controls. In these three patients, the most striking shared facial feature is the bulbous nasal tip, which appears green, and the upturned nose with a broad base (which appears red because this part of the nose is hypoplastic when compared with controls). Patient 5 has a more triangular-shaped face, which is illustrated by the red areas on the lateral side of the face. In contrast, patient 1D has a round face (the lateral sides of the face are green). Patient 7C has a relatively hypoplastic midface and chin compared with controls. The full colour version of this figure is available at European Journal of Human Genetics online.

Mentions: The analyses of 3D images of patients 5, 1D and 7C are shown in Figure 4. These two males and one female were considered representative for the KBG syndrome. In these three patients, the most striking shared facial feature is the bulbous nasal tip and the upturned nose with a broad base. Patient 5 has a more triangular-shaped face. In contrast, patient 1D has a round face. This is in concordance with our observation that the face seems to evolve from round at a young age to triangular shaped at a later age. Patient 7C has a relatively hypoplastic midface and chin compared with controls.


Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Brunner HG, van Loon RL, Smeets EE, van Haelst MM, van Haaften G, Nordgren A, Malmgren H, Grigelioniene G, Vermeer S, Louro P, Ramos L, Maal TJ, van Heumen CC, Yntema HG, Carels CE, Kleefstra T - Eur. J. Hum. Genet. (2014)

Two-dimensional clinical photographs and 3D stereophotogrammetry images of patients 5 (a), 1D (b) and 7C (c) are shown which were analysed and compared with composite faces of age- and sex-matched unaffected Dutch controls. Regions in green depict facial structures that are more prominent in the KBG syndrome patients. Red areas are more prominent in controls. In these three patients, the most striking shared facial feature is the bulbous nasal tip, which appears green, and the upturned nose with a broad base (which appears red because this part of the nose is hypoplastic when compared with controls). Patient 5 has a more triangular-shaped face, which is illustrated by the red areas on the lateral side of the face. In contrast, patient 1D has a round face (the lateral sides of the face are green). Patient 7C has a relatively hypoplastic midface and chin compared with controls. The full colour version of this figure is available at European Journal of Human Genetics online.
© Copyright Policy
Related In: Results  -  Collection

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fig4: Two-dimensional clinical photographs and 3D stereophotogrammetry images of patients 5 (a), 1D (b) and 7C (c) are shown which were analysed and compared with composite faces of age- and sex-matched unaffected Dutch controls. Regions in green depict facial structures that are more prominent in the KBG syndrome patients. Red areas are more prominent in controls. In these three patients, the most striking shared facial feature is the bulbous nasal tip, which appears green, and the upturned nose with a broad base (which appears red because this part of the nose is hypoplastic when compared with controls). Patient 5 has a more triangular-shaped face, which is illustrated by the red areas on the lateral side of the face. In contrast, patient 1D has a round face (the lateral sides of the face are green). Patient 7C has a relatively hypoplastic midface and chin compared with controls. The full colour version of this figure is available at European Journal of Human Genetics online.
Mentions: The analyses of 3D images of patients 5, 1D and 7C are shown in Figure 4. These two males and one female were considered representative for the KBG syndrome. In these three patients, the most striking shared facial feature is the bulbous nasal tip and the upturned nose with a broad base. Patient 5 has a more triangular-shaped face. In contrast, patient 1D has a round face. This is in concordance with our observation that the face seems to evolve from round at a young age to triangular shaped at a later age. Patient 7C has a relatively hypoplastic midface and chin compared with controls.

Bottom Line: Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity.Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent.As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.

No MeSH data available.


Related in: MedlinePlus