KBG syndrome: An Australian experience

Abstract

In 2011, heterozygous mutations in the ANKRD11 gene were identified in patients with KBG syndrome. Since then, 100 cases have been described with the expansion of the clinical phenotype. Here we present 18 KBG affected individuals from 13 unrelated families, 16 with pathogenic mutations in the ANKRD11 gene. Consistent features included intellectual disability, macrodontia, and the characteristic broad forehead with hypertelorism, and a prominent nasal bridge. Common features included hand anomalies, cryptorchidism, and a large number of palate abnormalities. Distinctive findings in this series included malrotation of the abdominal viscera, bilateral inguinal herniae in two patients, basal ganglia calcification and the finding of osteopenia in three patients. Nine novel heterozygous variants were found and the genotype-phenotype correlation was explored. This report highlights the need for thorough examination and investigation of the dental and skeletal systems. The results confirm the specificity of ANKRD11 mutations in KBG and further evidence for this transcription repressor in neural, cardiac, and skeletal development. The description of further cases of KBG syndrome is needed to further delineate this condition, in particular the specific neurological and behavioral phenotype.

Novel Mutations and Unreported Clinical Features in KBG Syndrome

“…No patients had a recognized diagnosis of autism spectrum disorder. Reports of this disorder in KBG are heterogeneous; it was reported to be as high as 47% by some authors , but much lower by others [Murray et al, 2017]. This difference may be due to varying ascertainment practices and referrals in different countries; such variability has already been noted for other conditions [Schneider et al, 2014].…”

“…Eight major criteria were initially defined (macrodontia of the upper central permanent incisors, characteristic facial appearance, hand anomalies, neurological involvement, delayed bone age, costovertebral anomalies, short stature, and the presence of a first-degree relative with KBG syndrome) [Skjei et al, 2007]. Later on, delayed bone age and costovertebral anomalies were suggested to be removed, and macrodontia was not considered a mandatory criterion any longer Low et al, 2016;Murray et al, 2017]. Minor features that can further help to establish a clinical diagnosis are otitis media and hearing impairment, seizures, cryptorchidism, feeding problems, palatal insufficiency, and delayed anterior fontanelle closure [Low et al, 2016].…”

“…Although diagnostic criteria have been proposed by several authors, there is no consensus on the clinical diagnostic criteria for KBG [Skjei et al, 2007;Low et al, 2016;Murray et al, 2017]. Eight major criteria were initially defined (macrodontia of the upper central permanent incisors, characteristic facial appearance, hand anomalies, neurological involvement, delayed bone age, costovertebral anomalies, short stature, and the presence of a first-degree relative with KBG syndrome) [Skjei et al, 2007].…”

KBG syndrome: Common and uncommon clinical features based on 31 new patients

“…A distinctive neurocognitive and behavioral profile has been delineated (Lo‐Castro et al, ). Herrmann, Pallister, Tiddy, and Opitz () first described this disorder, whose clinical phenotype has been expanded by subsequent studies (Brancati et al, ; Brancati, Sarkozy, & Dallapiccola, ; Goldenberg et al, ; Kleyner et al, ; Low et al, ; Murray et al, ; Ockeloen et al, ; Parenti et al, ; Reynaert et al, ; Zollino et al, ).…”

KBG syndrome in two patients from Egypt

“…Although large series of patients with various variants in ANKRD11 gene have been reported worldwide (Goldenberg et al, ; Low et al, ; Murray et al, ; Ockeloen et al, ), it has not been reported in Egyptian patients before. Here we report two unrelated patients with special emphasis on the orodental findings.…”