KBG Syndrome is a rare genetic condition characterized by a combination of physical traits, developmental delays, and skeletal anomalies. The syndrome’s name is derived from the initials of the three families first diagnosed in 1975. As a congenital disorder, its signs are typically present from birth, though some features, such as dental and cognitive issues, become more apparent as the child grows.
The Genetic Cause
KBG Syndrome is caused by alterations in the ANKRD11 gene, which is located on chromosome 16. This gene provides instructions for making the ankyrin repeat domain-containing protein 11, a key epigenetic regulator. The protein functions as a “master conductor” that helps control the activity of many other genes, particularly those involved in proper brain and bone development.
The genetic changes are typically loss-of-function alterations, such as sequence variations or deletions. This results in haploinsufficiency, where having only one functional copy of the ANKRD11 gene is not enough for normal development. The resulting reduction in functional protein disrupts the complex network of gene expression required for various bodily systems.
The condition follows an autosomal dominant inheritance pattern, meaning a person only needs one altered copy of the gene to be affected. While it can be inherited, approximately two-thirds of cases arise from a de novo mutation, a new genetic change that occurs spontaneously in the affected individual.
Key Physical and Developmental Features
The clinical presentation of KBG Syndrome is variable, but characteristic features aid identification. A distinctive and highly prevalent feature is macrodontia, the presence of unusually large permanent upper central incisors, observed in 85% to 95% of individuals. Other craniofacial characteristics often include a triangular face shape, prominent or bushy eyebrows, and widely spaced eyes.
Short stature is a frequent finding, affecting 40% to 77% of those diagnosed. Skeletal anomalies are also common, such as delayed bone age, meaning a child’s bones appear younger than their chronological age. Affected individuals may present with abnormalities in the bones of the hands and feet, including fifth-finger curvature (clinodactyly) or unusually short fingers (brachydactyly).
The syndrome almost universally includes neurodevelopmental involvement, presenting as delays in achieving motor and mental milestones. Intellectual disability is common, typically ranging from mild to moderate severity. Speech delay is often one of the first and most marked developmental issues.
Behavioral characteristics are also recognized clinical features. These can include hyperactivity, anxiety, and features consistent with an autism spectrum disorder. Less common associated issues involve hearing loss, seizures, and congenital heart defects, emphasizing the syndrome’s impact on multiple body systems.
Diagnosis and Management Approaches
The identification of KBG Syndrome begins with a thorough clinical evaluation, looking for the characteristic combination of physical and developmental features. Suspicion is raised by the presence of macrodontia, short stature, skeletal abnormalities, and intellectual disability. Confirmation requires molecular genetic testing.
Genetic testing involves analyzing the ANKRD11 gene for a pathogenic variant. This can be done through targeted sequencing, a gene panel, or whole exome sequencing. A chromosomal microarray may also detect a microdeletion on chromosome 16q24.3, which includes the ANKRD11 gene.
Management requires a multidisciplinary approach focused on symptoms, as there is no treatment for the underlying genetic cause. Initial assessments typically include:
- A systematic echocardiogram to check for heart defects.
- A palatal assessment.
- Comprehensive vision and hearing screens.
Ongoing care involves a team of specialists to address variable symptoms. This includes speech, physical, and occupational therapies to support developmental progress. Educational support is important for managing learning difficulties. Dental monitoring manages macrodontia and orthodontic issues, while an endocrinologist may monitor growth and address short stature.