Novel Mutations and Unreported Clinical Features in KBG Syndrome

Abstract

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.

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

“…Proportionate short stature is regarded as a major manifestation of KBG syndrome, spontaneous catch‐up growth beyond childhood appears limited, and growth hormone treatment is promising (Reynaert et al, ; Scarano et al, ). Precocious puberty could contribute to short stature, recommending monitoring of early signs of puberty (Scarano et al, )…”

“…Most common anatomic defects include septal defects, atrioventricular canal defect, and valvulopathies (Goldenberg et al, ; Low et al, ; Scarano et al, ). The association with atrioventricular canal defect seems quite specific (Digilio, Marino, Toscano, Giannotti, & Dallapiccola, ; Goldenberg et al, ; Low et al, )…”

DYSMORPHIC features and adult short stature: possible clinical markers of KBG syndrome

“…KBG syndrome was initially thought to be quite rare; however, it is likely underdiagnosed because many of its features are often mild and non-specific, and none of them are a prerequisite for the diagnosis [ 11 ]. To date, almost 200 subjects affected by the syndrome have been reported [ 12 ]. Although several familiar cases have been described, most of the affected individuals have novel de novo mutations.…”

“…Eight major clinical criteria were initially defined: macrodontia of the upper central permanent incisors (which is reported in 85–95% of affected individuals), characteristic facial appearance, hand anomalies, neurological involvement, delayed bone age, costovertebral anomalies, SS, and the presence of a first-degree relative with KBG syndrome [ 8 ]. Afterwards, delayed bone age and costovertebral anomalies were suggested to be removed, and macrodontia was not considered a mandatory criterion any longer [ 12 – 16 ]. 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 [ 14 ].…”

“…In this way, patients could benefit from early multidisciplinary interventions allowing better outcomes, especially with regards to growth and neurocognitive performances. Overall, with appropriate management, the prognosis of the syndrome is good [ 12 ].…”