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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

Clinical, intra-oral photographs and OPGs of three patients from family 1 (a–c), patient 4 (d), 6 (e), 2 (f), 8 (g), 9 (h) and 3 (i). All patients show macrodontia of upper central incisors. Patient 1D (a) shows macrodontia of central upper incisors and hypodontia of four permanent teeth. Patient 1B (b) shows macrodontia of four upper incisors, as well as talon cusps and dental crowding. Patient 1C (c) shows macrodontia of four upper incisors and hypodontia of four permanent teeth. Patients 4 and 6 (d and e) have no dental abnormalities except for macrodontia of upper central incisors (with a mesiodistal width ≥9.7 mm in both patients). Patient 2 (f) has macrodontia of the central upper incisors and talon cusps. Patient 8 (g) has rather large, mesially inclined central incisors and premature loss of the upper deciduous canines most probably due to crowding. Patient 9 (h) has macrodontia of upper central incisors and enamel defects. Dental anomalies of patient 3 (i) consist of macrodontia of four upper incisors and four lower incisors, as well as hypodontia of four premolars.
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fig2: Clinical, intra-oral photographs and OPGs of three patients from family 1 (a–c), patient 4 (d), 6 (e), 2 (f), 8 (g), 9 (h) and 3 (i). All patients show macrodontia of upper central incisors. Patient 1D (a) shows macrodontia of central upper incisors and hypodontia of four permanent teeth. Patient 1B (b) shows macrodontia of four upper incisors, as well as talon cusps and dental crowding. Patient 1C (c) shows macrodontia of four upper incisors and hypodontia of four permanent teeth. Patients 4 and 6 (d and e) have no dental abnormalities except for macrodontia of upper central incisors (with a mesiodistal width ≥9.7 mm in both patients). Patient 2 (f) has macrodontia of the central upper incisors and talon cusps. Patient 8 (g) has rather large, mesially inclined central incisors and premature loss of the upper deciduous canines most probably due to crowding. Patient 9 (h) has macrodontia of upper central incisors and enamel defects. Dental anomalies of patient 3 (i) consist of macrodontia of four upper incisors and four lower incisors, as well as hypodontia of four premolars.

Mentions: Macrodontia of upper permanent central incisors was present in all patients except patient 5, who was still in his transitional dentition. In patient 1D, macrodontia of the deciduous as well as the permanent dentition was observed as is shown in Figure 2. In patients 1B, 1C, 2, 3 and 9, macrodontia of other teeth, namely upper laterals and lower incisors, was noted as well. Hypodontia was seen in patients 1C and 1D and patient 3 (all of whom missed all four second premolars). Talon cusps were present in patients 1B, 1C and 2. Other dental anomalies were crowding (patient 1B), enamel hypoplasia (patient 9) and large dental pulps (patient 10). The dentofacial features of three patients of family 1, as well as patients 2, 3, 4, 6, 8 and 9 are shown in Figure 2. The dentofacial features of patient 13 with a 16q24 microdeletion are shown in Figure 3: the MRI image shows macrodontia of the permanent upper central incisors. The 2D clinical photograph (Figure 3) shows large upper central incisors in the deciduous dentition.


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)

Clinical, intra-oral photographs and OPGs of three patients from family 1 (a–c), patient 4 (d), 6 (e), 2 (f), 8 (g), 9 (h) and 3 (i). All patients show macrodontia of upper central incisors. Patient 1D (a) shows macrodontia of central upper incisors and hypodontia of four permanent teeth. Patient 1B (b) shows macrodontia of four upper incisors, as well as talon cusps and dental crowding. Patient 1C (c) shows macrodontia of four upper incisors and hypodontia of four permanent teeth. Patients 4 and 6 (d and e) have no dental abnormalities except for macrodontia of upper central incisors (with a mesiodistal width ≥9.7 mm in both patients). Patient 2 (f) has macrodontia of the central upper incisors and talon cusps. Patient 8 (g) has rather large, mesially inclined central incisors and premature loss of the upper deciduous canines most probably due to crowding. Patient 9 (h) has macrodontia of upper central incisors and enamel defects. Dental anomalies of patient 3 (i) consist of macrodontia of four upper incisors and four lower incisors, as well as hypodontia of four premolars.
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Related In: Results  -  Collection

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fig2: Clinical, intra-oral photographs and OPGs of three patients from family 1 (a–c), patient 4 (d), 6 (e), 2 (f), 8 (g), 9 (h) and 3 (i). All patients show macrodontia of upper central incisors. Patient 1D (a) shows macrodontia of central upper incisors and hypodontia of four permanent teeth. Patient 1B (b) shows macrodontia of four upper incisors, as well as talon cusps and dental crowding. Patient 1C (c) shows macrodontia of four upper incisors and hypodontia of four permanent teeth. Patients 4 and 6 (d and e) have no dental abnormalities except for macrodontia of upper central incisors (with a mesiodistal width ≥9.7 mm in both patients). Patient 2 (f) has macrodontia of the central upper incisors and talon cusps. Patient 8 (g) has rather large, mesially inclined central incisors and premature loss of the upper deciduous canines most probably due to crowding. Patient 9 (h) has macrodontia of upper central incisors and enamel defects. Dental anomalies of patient 3 (i) consist of macrodontia of four upper incisors and four lower incisors, as well as hypodontia of four premolars.
Mentions: Macrodontia of upper permanent central incisors was present in all patients except patient 5, who was still in his transitional dentition. In patient 1D, macrodontia of the deciduous as well as the permanent dentition was observed as is shown in Figure 2. In patients 1B, 1C, 2, 3 and 9, macrodontia of other teeth, namely upper laterals and lower incisors, was noted as well. Hypodontia was seen in patients 1C and 1D and patient 3 (all of whom missed all four second premolars). Talon cusps were present in patients 1B, 1C and 2. Other dental anomalies were crowding (patient 1B), enamel hypoplasia (patient 9) and large dental pulps (patient 10). The dentofacial features of three patients of family 1, as well as patients 2, 3, 4, 6, 8 and 9 are shown in Figure 2. The dentofacial features of patient 13 with a 16q24 microdeletion are shown in Figure 3: the MRI image shows macrodontia of the permanent upper central incisors. The 2D clinical photograph (Figure 3) shows large upper central incisors in the deciduous dentition.

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