ESPE Abstracts (2018) 89 P-P2-274

aRare Diseases and Auxological Unit, Department of Pediatrics, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; bUnit of Medical Genetics, Department of Medical and Surgical Science, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

KBG syndrome (OMIM 148050) is a an emerging autosomal dominant disorder caused by heterozygous mutations in the ANKRD11 gene or deletions of 16q24.3, characterized by developmental delay, short stature, dysmorphic facial features and skeletal anomalies. Patients and methods: We report 22 patients with dysmorphic features, learning disabilities, behavior problems and macrodontia, where a clinical diagnosis of KBG was suspected. An ANKRD11 defect was confirmed in 12 patients. In this group, 9 patients showed a point mutation in ANKRD11 gene and 3 patients carried a 16q24.3 deletion.

Results: All KBG patients presented facial dysmorphisms with typical nose-mouth appearances. Macrodontia is highly suggestive of this syndrome but not specific. Skeletal abnormalities were constant, in particular costo-vertebral abnormalities, and the majority of patients showed joint stiffness. Stature was <10th centile in 75% of the patients, 3 patients required GH treatment and 2 of these showed GH deficit. GH-therapy caused a significant increase of height velocity. Advanced puberty was reported in 28,5% males patients ANKRD11+ in peripubertal age. Due to its potential effect on growth, early signs of puberty must be carefully monitored in patients diagnosed at a young age. Cerebral structural abnormalities were seen in 8 patients. Developmental delay was reported in 83.3% patients, especially speech delay (75%) and learning difficulties. Language delay and ID are not related with the degree of intellectual disability and are non specific for the condition. In agreement with previously reported cases, all patients showed behavioral abnormalities (hyperactivity, attention deficit, anxiety, lack of self-confidence, frustration intolerance, aggressiveness and depression). Two patients had hematological abnormalities. Retrospectively, patients with negative genetic results had less typical clinical features. One patient showed a causative RAD21 mutation, confirming phenotypic overlap with cohesinopathies, and another one harbored a large de novo duplication of 12.q21.1-q21.33. The remaining eight patients are at present undiagnosed.

Conclusions: We emphasize that genetic analysis of ANKRD11 can easily reach a detection rate higher than 50% thanks to clinical phenotyping, particularly facial appearance. Joint stiffness was not reported previously but seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up. We recommend echocardiogram, renal ultrasonography, ophthalmic, and hearing assessments and good dental care along with formal developmental assessments and appropriate early intervention.

References: 1) Herrmann J et al: The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Art Ser 11:7–18 (1975).

2) Low K et al: Clinical and Genetic Aspects of KBG syndrome. Am J Med Genet 170:2835–2846 (2016).

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