The journey to understanding a child’s health and development can sometimes involve a long and frustrating search for answers, especially when they present with a unique combination of developmental delays, short stature, and subtle physical differences. For many families, a diagnosis of KBG syndrome finally provides a name and a unifying explanation for these challenges. KBG syndrome is a rare genetic disorder that affects skeletal development, growth, and cognitive function. Because it is so rare and its features can be variable, it is often underdiagnosed. Receiving this diagnosis can be overwhelming, but it is the critical first step that allows families to move from uncertainty to action, enabling them to build a supportive care plan designed to help their child navigate their challenges and thrive.

KBG syndrome is a rare congenital disorder characterized by a constellation of features, most notably distinctive facial characteristics, abnormally large upper front teeth (macrodontia), skeletal abnormalities, and some degree of developmental delay. It is a spectrum disorder, meaning the signs and symptoms can vary significantly in their combination and severity from one person to another.

At its core, KBG syndrome is a disorder of gene regulation. To understand this, it is helpful to use an analogy.

• Think of your DNA as a massive library containing thousands of individual cookbooks (your genes). Each cookbook holds the recipes for building the proteins that make up your body.
• However, just having the cookbooks is not enough. The library needs a sophisticated system to control which recipes are used, how often they are read, and at what times during development. This control is managed by a team of “master conductors” or epigenetic regulators.
• The gene affected in KBG syndrome is responsible for making one of these crucial conductors. This conductor’s job is not to be a recipe itself, but to guide the entire orchestra of other genes, telling them when to turn on and off to ensure proper development.
• In KBG syndrome, a mutation means this conductor is faulty. It cannot properly direct the symphony of development. As a result, the processes that guide the formation of the skeleton, teeth, and brain are disrupted, leading to the specific set of features seen in the syndrome.

In my experience, parents often seek answers after noticing a mix of developmental delays and distinctive facial features. KBG syndrome is one of those rare genetic conditions that isn’t immediately recognized.

The cause of KBG syndrome is a mutation or a deletion involving the ANKRD11 gene, which is located on chromosome 16. The protein produced by the ANKRD11 gene is a key epigenetic regulator. It acts as a “co-regulator,” interacting with other proteins to control the activity (expression) of a wide range of other genes that are essential for:

• Normal skeletal development and bone maturation.
• The proper formation of teeth.
• Healthy neurological development and cognitive function.

When one copy of the ANKRD11 gene is lost or mutated, the body cannot produce enough of this critical conductor protein. This “haploinsufficiency” disrupts the normal gene expression program, leading to the characteristic features of KBG syndrome.

In my experience, families are often surprised to learn it’s a genetic mutation, not something acquired during pregnancy or infancy which can be passed down, even if mild in a parent.

KBG syndrome is a genetic disorder. It is not contagious and cannot be acquired. Its inheritance pattern is a key point of understanding for families.

• Autosomal Dominant Inheritance: KBG syndrome is inherited in an autosomal dominant pattern. This means that an individual only needs to inherit one copy of the mutated ANKRD11 gene to be affected by the syndrome.
• Sporadic (de novo) Mutation: In the majority of cases, KBG syndrome is caused by a de novo (new) mutation. This means the genetic change is a random error that occurred for the first time in the child, either in the egg or sperm cell of a parent or very early after fertilization. In these cases, there is no prior family history of the disorder, and the parents have normal genes. It is crucial for parents to understand that there is nothing they did or did not do to cause a de novo mutation.
• Inherited Form: In some cases, the condition is inherited from a parent who also has KBG syndrome. Because the features of the syndrome can be very subtle and variable, it is not uncommon for a parent to be diagnosed with a mild form of KBG syndrome only after their more obviously affected child receives a diagnosis. An affected parent has a 50% chance of passing the condition on to each of their children.

Clinically, I’ve seen some children diagnosed only after a younger sibling shows similar traits highlighting the variability of expression even within the same family.

Clinical features of KBG syndrome are highly variable. Some individuals may have very subtle signs, while others have more significant involvement.

The most characteristic signs and symptoms include the following:

Hallmark Physical Features:

• Macrodontia: The most distinctive and consistent feature is having unusually large upper central incisors (the two front teeth).
• Distinctive Facial Features: Many individuals share a recognizable facial appearance, which can include a triangular-shaped face, prominent eyebrows, widely spaced eyes (hypertelorism), a prominent nasal bridge, and a thin upper lip.
• Skeletal Abnormalities:
  • Delayed bone age is very common in childhood, meaning a child’s skeletal maturity is behind their chronological age.
  • Short stature is seen in many individuals.
  • Abnormalities of the spine and ribs (costovertebral anomalies).
  • Hand anomalies, such as short fingers (brachydactyly) or curved pinky fingers (clinodactyly).

Developmental and Neurological Features:

• Developmental Delay: This is a nearly universal feature. Children with KBG often experience delays in reaching motor milestones (like sitting and walking) and, particularly, speech and language milestones.
• Intellectual Disability: Most individuals with KBG syndrome have some degree of intellectual disability, but it is typically in the mild to moderate range. Many individuals are able to learn, attend school with support, and live semi-independently as adults.
• Seizures: Epilepsy can occur in some individuals with the syndrome.
• Behavioral Characteristics: Some individuals may have behavioral challenges, including features of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder.

Other Common Medical Issues:

• Feeding Difficulties: Significant feeding problems are very common in infancy and early childhood, often due to low muscle tone.
• Hearing Loss: Both conductive (related to the bones of the middle ear) and sensorineural (related to the auditory nerve) hearing loss can occur.
• Congenital Heart Defects: While less common than in some other syndromes, structural heart problems can be present.

Clinically, I look for hallmark signs like macrodontia of the upper central incisors, hand anomalies, and mild skeletal findings such as delayed bone age or costovertebral abnormalities.

For years, KBG syndrome was considered extremely rare, largely because it was difficult to diagnose. The diagnosis was made clinically by a geneticist who could recognize the subtle constellation of features. Today, the widespread availability of advanced genetic testing has made diagnosis much more accessible and definitive.
The diagnostic journey often begins when a child is evaluated for developmental delay or short stature.

1. Clinical Examination: A doctor or clinical geneticist will perform a thorough physical examination, looking for the characteristic features of the syndrome, particularly the combination of distinctive facial features, macrodontia, and skeletal anomalies.
2. Skeletal X-rays: X-rays of the spine and hands may be ordered to look for delayed bone age and the specific vertebral and hand anomalies associated with KBG syndrome.
3. Molecular Genetic Testing: The diagnosis of KBG syndrome is definitively confirmed with a molecular genetic test.
   • A blood sample is taken, and a doctor will typically order a broad genetic test, such as Whole Exome Sequencing (WES) or a comprehensive gene panel for developmental delay.
   • These tests analyze thousands of genes at once and can identify a disease-causing mutation or deletion in the ANKRD11 gene. A positive result confirms the diagnosis.

Once a diagnosis is confirmed, a child should undergo a comprehensive evaluation to screen for potential associated health issues. This should include a formal hearing test, an eye exam, an echocardiogram of the heart, and a developmental assessment.

In my experience, early involvement of a geneticist is key especially when the presentation overlaps with other neurodevelopmental or craniofacial syndromes.

There is no cure for the underlying genetic cause of KBG syndrome. Therefore, management is entirely supportive and symptomatic. The goal is to address each individual’s specific medical, developmental, and educational needs to help them achieve their full potential. This requires a proactive and coordinated multidisciplinary team.

The key management strategies include:

• Early Intervention and Developmental Therapies: This is the absolute cornerstone of management for a child with KBG syndrome. Starting therapies as early as possible can make a significant difference in a child’s developmental trajectory.
  • Speech and Language Therapy is critical to address the significant communication delays. This may include exploring alternative communication methods.
  • Physical Therapy helps to manage low muscle tone, improve gross motor skills, and address any skeletal issues like scoliosis.
  • Occupational Therapy helps with fine motor skills, sensory processing challenges, and learning the skills needed for daily living.
• Educational Support: Most children with KBG syndrome will require and benefit from an individualized education plan (IEP) and special education services within a supportive school environment.
• Dental and Orthodontic Care: Regular dental care is crucial. Orthodontic treatment may be needed to manage the macrodontia and any associated crowding or bite issues.
• Hearing Management: Regular hearing screenings are essential. If hearing loss is detected, the use of hearing aids or other assistive devices is important for language development.
• Endocrine Management: An endocrinologist will monitor the child’s growth. In some cases of significant short stature, growth hormone therapy may be considered, although its effectiveness is still being studied for this specific syndrome.
• Management of Other Medical Issues: This includes managing seizures with a neurologist if they are present, and regular follow-up with other specialists as needed.

I’ve found that multidisciplinary care, speech therapy, occupational therapy, behavioral support, and regular dental and neurological evaluations offer the best outcomes.

KBG syndrome is a rare genetic disorder caused by mutations in the ANKRD11 gene, characterized by a unique combination of macrodontia, skeletal anomalies, and developmental delay. For many families, the journey to this diagnosis is a long one, as the features can be subtle and variable. However, receiving a definitive diagnosis, most often through modern genetic testing, provides crucial answers and a clear path forward. While there is no cure for the underlying genetic cause, KBG syndrome is a condition that can be proactively managed. A strong, multidisciplinary team focused on early and intensive developmental therapies, dental care, and monitoring for associated health issues is the key to a positive outcome. In my experience, early diagnosis of KBG syndrome provides families with clarity and access to supportive resources that can significantly improve long-term developmental outcomes.

1. National Organization for Rare Disorders (NORD). (2022). KBG Syndrome. Retrieved from https://rarediseases.org/rare-diseases/kbg-syndrome/
2. National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). KBG syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/10972/kbg-syndrome
3. The KBG Foundation. (n.d.). About KBG Syndrome. Retrieved from https://www.kbgfoundation.com/about-kbg-syndrome