Diagnosing KBG syndrome involves recognizing a constellation of physical features and developmental patterns, followed by genetic testing to confirm the diagnosis. While there are no formal consensus criteria, understanding the key clinical signs and available testing options helps families and healthcare professionals navigate the diagnostic journey for this rare genetic condition.

Introduction: When to Seek Diagnostic Evaluation

Parents and caregivers may first notice something unusual about their child’s development or appearance during infancy or early childhood. KBG syndrome should be considered when a child shows a combination of developmental delays, distinctive facial features, unusually large front teeth, and growth concerns. Because the presentation of KBG syndrome can vary significantly from one person to another, some individuals may have very mild features that go unrecognized for years, while others display more obvious signs from birth.^[1]

Children who are not meeting typical developmental milestones, such as speaking or walking later than expected, may benefit from diagnostic evaluation. Similarly, if a child has short stature along with certain facial characteristics—like a triangular face shape, widely spaced eyes, or eyebrows that grow together in the middle—healthcare providers may recommend further investigation. Some affected individuals may also experience feeding difficulties as infants, skeletal abnormalities noticed during routine examinations, or behavioral challenges that prompt medical attention.^[2]

It is important to understand that KBG syndrome is often underdiagnosed because its signs and symptoms can be mild and may initially be attributed to other, more common conditions. For unknown reasons, males tend to be affected more often and more severely than females, which can further complicate recognition of the syndrome in girls or women with subtle features. Because early diagnosis can lead to appropriate monitoring and intervention for potential complications, seeking evaluation when multiple concerning features are present can make a meaningful difference in long-term care.^[1]

Diagnostic Methods

Clinical Evaluation and Physical Examination

The diagnostic process typically begins with a detailed clinical evaluation conducted by a healthcare professional. During this assessment, the doctor will take a comprehensive medical history, asking about when symptoms first appeared, which developmental milestones have been reached or delayed, and whether there is any family history of similar features. This information helps create a complete picture of the child’s health and development over time.^[8]

A thorough physical examination is a critical part of the diagnostic process. The healthcare provider will carefully assess the child’s facial features, looking for characteristic signs such as a triangular face shape, a wide and short skull (called brachycephaly), widely spaced eyes, eyebrows that may grow together in the middle, a prominent bridge of the nose, a long space between the nose and upper lip, and a thin upper lip. One of the hallmark features of KBG syndrome is unusually large upper front teeth, known as macrodontia, though this feature may not be visible until the permanent teeth come in, typically around age six or seven.^[2]

The physical examination also includes assessment of growth parameters. Most individuals with KBG syndrome are shorter than average from birth, and healthcare providers will measure height, weight, and head circumference and compare these measurements to standard growth charts. The doctor may also examine the hands and feet for skeletal abnormalities, such as unusually short or curved pinky fingers, which are common in affected individuals. A complete physical examination may reveal other features like flat feet, abnormalities of the spine or ribs, or signs of delayed closure of the soft spot on a baby’s head.^[1]

Dental Assessment

Because macrodontia—especially of the permanent upper central incisors—is observed in approximately 80% of individuals with KBG syndrome, dental evaluation can provide valuable diagnostic information. However, this feature is not visible until the permanent teeth erupt, which typically occurs in early school age. Additional dental findings may include missing teeth, premature loss of teeth in adults, and problems with tooth enamel. A dental assessment documenting these features can support the clinical suspicion of KBG syndrome.^[8]

Developmental and Behavioral Assessment

Most individuals with KBG syndrome experience developmental delays and mild to moderate intellectual disability. Healthcare providers will assess the child’s developmental progress, including speech and language development, motor skills, and cognitive abilities. Parents may be asked to complete questionnaires about their child’s development, and the child may undergo formal developmental testing. Because behavioral issues such as hyperactivity, anxiety, and characteristics of autism spectrum disorder are common in KBG syndrome, a comprehensive evaluation may also include behavioral and psychological assessment.^[8]

Skeletal and Imaging Studies

Imaging studies can provide additional diagnostic information about skeletal features associated with KBG syndrome. An X-ray of the hand and wrist is commonly performed to assess bone age. In KBG syndrome, there is typically slowed mineralization of bones, resulting in delayed bone age—for example, a three-year-old child might have bones that look more typical of a two-year-old. This finding is common but not specific to KBG syndrome. X-rays may also reveal abnormalities of the bones of the spine, ribs, hands, or feet.^[1]

Genetic Testing

While clinical evaluation can suggest a diagnosis of KBG syndrome, genetic testing is the only way to confirm it definitively. The diagnosis is established by identifying either a change (called a pathogenic variant or mutation) in the ANKRD11 gene or a deletion of genetic material at chromosome location 16q24.3 that includes the ANKRD11 gene.^[2]

Several different genetic testing methods can be used to identify these changes. Array-comparative genome hybridization (a-CGH) is a technique that can detect deletions or duplications of genetic material. Targeted sequencing focuses specifically on the ANKRD11 gene to look for mutations. Gene panel testing examines multiple genes associated with developmental disorders simultaneously, which can be helpful when the diagnosis is uncertain. Whole exome sequencing or whole genome sequencing examines all or most of a person’s genes and can identify changes that might be missed by more targeted approaches.^[8]

The vast majority of genetic changes identified in KBG syndrome are loss-of-function variants, meaning they lead to a reduced or absent function of the ANKRD11 protein. These include nonsense variants (which introduce a premature stop signal in the genetic instructions) and frameshift variants (which disrupt the normal reading frame of the gene). Larger deletions that remove part or all of the ANKRD11 gene can also cause the syndrome. It is worth noting that missense variants—changes that alter a single building block of the protein—should be interpreted with caution, as the vast majority of disease-causing variants in ANKRD11 result in loss of protein function.^[6]

Genetic testing for KBG syndrome is typically performed on a blood sample. In some cases, testing may reveal that one of the parents also carries the same genetic change, even if they have no symptoms or only very mild features. In other cases, the genetic change occurred for the first time in the affected individual, with no family history of the condition. Because KBG syndrome follows an autosomal dominant pattern of inheritance, only one copy of the altered gene is needed to cause the disorder.^[1]

Distinguishing KBG Syndrome from Other Conditions

Several other genetic conditions share some features with KBG syndrome, making it important for healthcare providers to consider alternative diagnoses during the evaluation process. Conditions that may need to be ruled out include Cornelia de Lange syndrome, which also causes distinctive facial features and developmental delays; cleidocranial dysplasia, which affects bone development; Robinow syndrome, characterized by skeletal abnormalities and distinctive facial features; and 22q11.2 deletion syndrome, which can cause a wide range of developmental and medical problems.^[8]

Genetic testing is often the most reliable way to distinguish KBG syndrome from these other conditions, as each has its own characteristic genetic changes. However, clinical evaluation by experienced healthcare providers familiar with these rare conditions can also provide valuable clues that point toward the correct diagnosis.

Additional Diagnostic Assessments

Once a diagnosis of KBG syndrome is confirmed or strongly suspected, additional assessments may be recommended to check for associated complications. An echocardiogram (ultrasound of the heart) may be performed to look for congenital heart defects, which can occur in some individuals with KBG syndrome. Hearing tests are important because hearing loss—which can be conductive (related to problems in the outer or middle ear), sensorineural (related to the inner ear or hearing nerve), or mixed—has been reported in affected individuals.^[2]

An electroencephalogram (EEG), which measures electrical activity in the brain, may be recommended if there are concerns about seizures, as seizure disorders can occur in KBG syndrome. Evaluation of the palate (roof of the mouth) is important because abnormalities are common and can affect feeding and speech. Depending on the individual’s symptoms, other specialized evaluations may be needed.^[2]

Diagnostics for Clinical Trial Qualification

While the diagnostic approach described above applies to general medical care, individuals interested in participating in clinical trials for KBG syndrome may need to undergo additional or more specific testing to determine whether they meet enrollment criteria. Clinical trials are research studies that test new approaches to treatment, and each trial has its own specific requirements for who can participate.^[2]

Genetic Confirmation

Most clinical trials for KBG syndrome will require genetic confirmation of the diagnosis through identification of a pathogenic variant in the ANKRD11 gene or a deletion at chromosome location 16q24.3 that includes this gene. This requirement ensures that all participants in the study truly have the condition being investigated. The genetic testing may need to be performed in a specific certified laboratory or documented in a particular format to meet trial requirements.^[2]

Standardized Clinical Assessments

Clinical trials typically use standardized assessment tools to measure the severity of symptoms and track changes over time. For KBG syndrome trials, these might include formal developmental or cognitive testing, behavioral assessments using validated questionnaires, and detailed measurements of growth parameters. Participants may need to undergo these assessments at specific time points before and during the trial.

Baseline Health Evaluations

Before enrolling in a clinical trial, participants typically undergo comprehensive baseline health evaluations to document their current health status and identify any conditions that might affect their participation. These evaluations help researchers understand each participant’s starting point and ensure that it is safe for them to participate in the study. For KBG syndrome, baseline assessments might include evaluation of hearing, vision, heart function, seizure history, and developmental status.

Because specific enrollment criteria vary widely depending on the particular clinical trial, families interested in clinical trial participation should discuss available opportunities and qualification requirements with their healthcare provider or contact clinical trial coordinators directly for detailed information about what testing and documentation will be needed.