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Mol Syndromol. 2019 May;10(3):130-138. doi: 10.1159/000496172. Epub 2019 Jan 15.

Novel Mutations and Unreported Clinical Features in KBG Syndrome.

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Rare Disease Unit, Department of Pediatrics, St. Orsola-Malpighi Hospital, Bologna, Italy.
Unit of Medical Genetics, Department of Medical and Surgical Sciences, University Alma Mater Studiorum, St. Orsola-Malpighi Hospital, Bologna, Italy.
Unit of Hygiene and Medical Statistics, Department of Biomedical and Neuromotor Sciences, University Alma Mater Studiorum, Bologna, Italy.
Laboratory of Medical Genetics, Bambino Gesù Pediatric Hospital, IRCCS, Rome, Italy.


KBG syndrome is an autosomal dominant disorder caused by pathogenic variants within ANKRD11 or deletions of 16q24.3 which include ANKRD11. It is characterized by distinctive facial features, developmental delay, short stature, and skeletal anomalies. We report 12 unrelated patients where a clinical diagnosis of KBG was suspected and confirmed by targeted analyses. Nine patients showed a point mutation in ANKRD11 (none of which were previously reported) and 3 carried a 16q24.3 deletion. All patients presented with typical facial features and macrodontia. Skeletal abnormalities were constant, and the majority of patients showed joint stiffness. Three patients required growth hormone treatment with a significant increase of height velocity. Brain malformations were identified in 8 patients. All patients showed behavioral abnormalities and most had developmental delay. Two patients had hematological abnormalities. We emphasize that genetic analysis of ANKRD11 can easily reach a detection rate higher than 50% thanks to clinical phenotyping, although it is known that a subset of ANKRD11-mutated patients show very mild features and will be more easily identified through the implementation of gene panels or exome sequencing. Joint stiffness was reported previously in few patients, but it seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up.


16q24.3 deletion; ANKRD11; Joint stiffness; KBG syndrome; Macrodontia

[Available on 2019-11-01]
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