KBG syndrome is a rare neurodevelopmental disorder that affects multiple body systems, leading to a variety of physical and intellectual differences. Classified as a congenital malformation syndrome, it is present from birth and involves structural or functional anomalies. It was first described in 1975, with the name KBG derived from the initials of the surnames of the first three families diagnosed. The syndrome is characterized by a combination of distinctive facial features, skeletal abnormalities, and developmental delays, though specific manifestations vary significantly among individuals.
The Genetic Basis
The underlying cause of KBG syndrome is a change in the ANKRD11 gene, located on chromosome 16 (16q24.3). This gene provides instructions for creating the Ankyrin Repeat Domain 11 protein, which functions as a transcriptional co-regulator managing the activity of other genes within the cell nucleus. This protein is important in regulating chromatin and gene expression during brain development.
A change in the ANKRD11 gene typically results in a loss-of-function, leading to haploinsufficiency, where one functional copy of the gene is insufficient.
KBG syndrome is inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is needed to develop the condition. While it can be passed down from an affected parent, many cases arise from de novo mutations. A de novo mutation is a spontaneous change that occurs for the first time in the affected individual and is not inherited.
Key Physical and Developmental Characteristics
The physical presentation of KBG syndrome is highly variable, but several features are frequently observed, particularly those affecting the head and skeleton. One of the most recognizable traits is macrodontia, characterized by unusually large upper central incisors, reported in 80% to 95% of individuals. Distinctive craniofacial features often include a triangular face shape, widely spaced eyes (hypertelorism), and broad or prominent eyebrows that may grow together (synophrys).
Skeletal differences are common, with many individuals exhibiting short stature, often falling below the 10th percentile for height. Delayed bone age is another frequent finding, meaning a child’s bone development is behind their chronological age. Abnormalities of the hands and feet, such as short fingers (brachydactyly) or an inward curvature of the fifth finger (clinodactyly), are also reported in many cases.
Neurodevelopmental challenges are a primary component of the syndrome, presenting as intellectual disability that ranges from mild to moderate in severity. Global developmental delay is nearly universal, with a marked delay in speech acquisition being a common early indicator. Behavioral differences, including hyperactivity (ADHD), anxiety, and features consistent with autism spectrum disorder, are also frequently observed.
Other body systems can be involved, though less consistently. Hearing loss, which can be conductive, sensorineural, or mixed, is seen in approximately 25% to 31% of affected individuals. Seizures affect a significant minority, estimated to occur in about 20% to 40% of patients, and heart defects have also been reported in some cases.
Diagnosis and Ongoing Management
The process of identifying KBG syndrome typically begins with a clinician suspecting the diagnosis based on the constellation of physical and developmental features. The presence of macrodontia, short stature, and global developmental delay often raises the initial clinical suspicion. Definitive confirmation of the diagnosis requires genetic testing to identify a pathogenic variant or deletion involving the ANKRD11 gene.
Genetic testing may involve specific sequencing of the ANKRD11 gene or a chromosomal microarray analysis to detect a microdeletion at the 16q24.3 location. Once the diagnosis is confirmed, management is supportive and requires a comprehensive, multidisciplinary approach tailored to the individual’s specific needs. Since the condition is genetic, there is no treatment that can reverse the underlying cause.
The care team often includes a pediatrician, a geneticist, a neurologist, and various specialists like dental surgeons and otolaryngologists. Supportive therapies are a cornerstone of long-term management, with speech therapy addressing communication delays and physical therapy helping with motor skill development. Occupational therapy provides assistance with fine motor skills and daily living activities, complemented by specialized educational support to address intellectual differences.
Routine monitoring is essential for managing associated medical conditions, including baseline screening for heart defects via an echocardiogram. Regular hearing and vision assessments are crucial, especially given the prevalence of hearing loss and potential for vision problems. Ongoing surveillance of growth, pubertal development, and behavioral health ensures that interventions are timely and personalized throughout the individual’s lifespan.