Cognitive and Adaptive Characterization of Children and Adolescents with KBG Syndrome: An Explorative Study

Alfieri, Paolo; Caciolo, Cristina; Lazzaro, Giulia; Menghini, Deny; Cumbo, Francesca; Dentici, Maria Lisa; Digilio, María Cristina; Gnazzo, Maria; Demaria, Francesco; Pironi, Virginia; Zampino, Giuseppe; Novelli, Antonio; Tartaglia, Marco; Vicari, Stefano

doi:10.3390/jcm10071523

Cited by 3 publications

(1 citation statement)

References 29 publications

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“…Height below average was present in 20/49 patients, while short stature (height < −2SD) was detected in 5/49 individuals. ID generally ranges from mild to moderate in line with previous reports ( 27 ) and seizures generally correlated with cerebral anomalies. The occurrence of cerebral anomalies suggests that performing a brain MRI might help reaching a diagnosis of KBGS.…”

Section: Discussionsupporting

confidence: 88%

Natural history of KBG syndrome in a large European cohort

Loberti

Bruno

Granata

et al. 2022

Human Molecular Genetics

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KBG syndrome is characterised by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterise natural history of KBG syndrome. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array-CGH and NGS approach investigated both genomic CNVs/SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while OFC (median value: −0.88 SD at birth) normalised over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia, and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ENT evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

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Section: Discussionsupporting

confidence: 88%

Natural history of KBG syndrome in a large European cohort

Loberti

Bruno

Granata

et al. 2022

Human Molecular Genetics

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To speak may draw on epigenetic writing and reading: Unravelling the complexity of speech and language outcomes across chromatin-related neurodevelopmental disorders

St John,

Tripathi,

Morgan

et al. 2023

Neuroscience & Biobehavioral Reviews

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Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search

He,

Zhang,

et al. 2024

Orphanet J Rare Dis

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Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

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Cognitive and Adaptive Characterization of Children and Adolescents with KBG Syndrome: An Explorative Study

Cited by 3 publications

References 29 publications

Natural history of KBG syndrome in a large European cohort

Natural history of KBG syndrome in a large European cohort

To speak may draw on epigenetic writing and reading: Unravelling the complexity of speech and language outcomes across chromatin-related neurodevelopmental disorders

Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search

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