KBG syndrome is a rare genetic condition caused by changes in the ANKRD11 gene, marked by distinctive facial features, unusually large upper front teeth, skeletal differences, and developmental delay that ranges from mild to moderate. Named after the initials of the first families described with it in 1975, the syndrome was long considered extremely rare, but genetic testing has revealed it is more common than once thought, with its subtle features often going unrecognized for years.
The Genetic Cause
KBG syndrome results from a disruption of the ANKRD11 gene on chromosome 16. Most cases involve protein-truncating variants, which are mutations that cut the gene’s protein product short, but missense variants that change a single building block of the protein can also cause the condition. In a study of 29 individuals, researchers identified 20 unique missense variants, most of them arising spontaneously rather than being inherited, and these produced a clinical picture similar to the truncating mutations.1PubMed. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein A smaller number of cases are caused by microdeletions at the 16q24.3 chromosomal region, which remove ANKRD11 along with neighboring genes.2PubMed. A Korean family with KBG syndrome identified by ANKRD11 mutation, and phenotypic comparison of ANKRD11 mutation and 16q24.3 microdeletion
Most mutations arise de novo, meaning neither parent carries the change. However, KBG syndrome follows an autosomal dominant inheritance pattern, so an affected parent has a 50 percent chance of passing it on. Familial transmission has been documented, including a report of two sisters and their mother all showing intellectual disability, short stature, and macrodontia consistent with the syndrome.3PubMed. Mental retardation, short stature, minor skeletal anomalies, craniofacial dysmorphism and macrodontia in two sisters and their mother Because affected parents can have mild features that were never formally diagnosed, genetic testing of family members is often worthwhile once a child is identified.
What ANKRD11 Does in the Developing Brain
The ANKRD11 protein acts as a chromatin regulator, meaning it helps control which genes get turned on or off during development. It does this in part by interacting with enzymes that add or remove chemical tags from histone proteins, the spools around which DNA is wound. When ANKRD11 is missing or malfunctioning, the balance of these tags is thrown off in neural precursor cells, leading to altered gene expression during brain development.4PubMed. Ankrd11 is a chromatin regulator involved in autism that is essential for neural development Downstream consequences include reduced activity of growth-factor signaling pathways important for neuron branching and maturation.5PubMed Central. ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway This explains why the syndrome’s most consistent effect is on cognitive development, but the same gene operates in bone, heart, and other tissues, which is why the syndrome affects multiple organ systems.
Recent research has also found that ANKRD11 interacts with cohesin, a protein complex best known for holding chromosomes together during cell division but also involved in gene regulation. A single engineered mutation that disrupted this interaction in mice produced neural and craniofacial abnormalities mirroring those seen in human patients.6PubMed Central. ANKRD11 binding to cohesin suggests a connection between KBG syndrome and Cornelia de Lange syndrome This finding hints at molecular overlap between KBG syndrome and Cornelia de Lange syndrome, another developmental condition tied to cohesin dysfunction.
Recognizing the Facial and Dental Features
The facial appearance in KBG syndrome is distinctive once you know what to look for, but it can be subtle enough that clinicians unfamiliar with the condition miss it. Common features include a broad or triangular face, wide-set eyes, a broad nasal bridge, a long or prominent philtrum (the groove between nose and upper lip), and full or bushy eyebrows. These features tend to become more recognizable with age but are never dramatic enough to be instantly obvious in a crowd.
The single most characteristic physical finding is macrodontia of the upper central permanent incisors, meaning the front teeth are significantly larger than expected. In one review of published cases, oral features appeared in 98 percent of patients, and macrodontia specifically was present in 96 percent.7PubMed. KBG syndrome: clinical features and specific dental findings Because permanent teeth do not erupt until around age six or seven, this hallmark sign is invisible in infants and toddlers, which is one reason early diagnosis is so difficult. Dentists who notice disproportionately large upper incisors in a child with developmental delay should consider referring the family for genetic evaluation.
Skeletal Differences
Skeletal anomalies are a core part of the syndrome and show up on X-rays far more often than they cause visible problems. In a study of 38 individuals with KBG syndrome, 92 percent had skeletal abnormalities on imaging. Spinal findings were the most frequent, present in about three-quarters of cases, with lordosis being the single most common individual finding. Rib (costal) anomalies appeared in about 40 percent.8PubMed. Expanding the Evaluation of Skeletal Anomalies in Patients With KBG Syndrome: Recommendations for Clinical Practice Patients with short stature tended to have higher rates of kyphosis and delayed bone age.
A deep-phenotyping study of 53 patients added that hand X-rays frequently reveal abnormalities in the carpal bones, including delayed maturation of those bones out of proportion to the rest of the hand.9PubMed Central. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature Other findings include scoliosis, coccygeal anomalies, and cervical ribs. Most skeletal differences do not require surgical intervention but should be monitored, especially scoliosis during growth spurts.
Neurodevelopment, Speech, and Behavior
Developmental delay or intellectual disability appears in virtually every confirmed case, though its severity varies widely. In a Korean series, all eight patients showed some degree of developmental delay or intellectual disability.10PubMed Central. KBG syndrome: Clinical features and molecular findings in seven unrelated Korean families with a review of the literature Speech is often the most affected domain. In a cohort of 23 patients, 81 percent had delayed speech, and 86 percent showed psychomotor hyperactivity.11PubMed Central. Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome A hoarse or low-pitched voice was noted in over half of patients in that study, which is an underappreciated clue that can point clinicians toward the diagnosis.
The behavioral profile is more specific than a generic “behavioral difficulties” label suggests. When researchers compared individuals with KBG syndrome to people with other intellectual disabilities, the KBG group showed more attentional problems, hyperactivity, and oppositional behavior, but fewer difficulties with social functioning. Cognitive testing revealed weaknesses in sustained attention, cognitive flexibility, and visual-spatial construction, alongside relative strengths in visual memory, social cognition, and emotion recognition.12PubMed Central. Exploring the behavioral and cognitive phenotype of KBG syndrome That last point is worth highlighting: earlier case reports sometimes described autism-like features, but systematic assessment found that social understanding is actually a relative strength. The impulsive, inattentive behavior may be better understood as executive dysfunction rather than a social cognition deficit.
Where the ANKRD11 mutation falls on the gene may influence severity. An analysis of Chinese patients and literature cases found that intellectual disability tended to be milder in patients whose truncating variant sat between certain functional domains of the protein compared to those whose mutation disrupted all major functional domains.13PubMed Central. Comprehensive analysis of clinical spectrum and genotype associations in Chinese and literature reported KBG syndrome This genotype-phenotype relationship is still being refined, but it offers some basis for individualized counseling.
Seizures and Brain Imaging Findings
Seizures are a common complication. A scoping review examining patients with epilepsy and KBG syndrome found that the median age for first seizure was four years, though the range was enormous, from the first month of life through age 51. Generalized tonic-clonic seizures were the most frequent type, followed by absences and focal seizures.14PubMed. KBG syndrome: A scoping review of electroclinical features of patients with epilepsy EEG abnormalities, even without clinical seizures, are commonly reported. One case study described an age-dependent slowing pattern in the posterior brain regions that appeared during childhood and resolved in adolescence, suggesting that some EEG findings may be transient.15Seizure. Electroclinical features and outcome of ANKRD11-related KBG syndrome
Brain MRI frequently reveals structural differences that were previously underappreciated. In a cohort of 53 patients, incomplete hippocampal inversion was found in about 63 percent and posterior fossa malformations in about 66 percent, rates far higher than earlier literature suggested. Other recurrent findings included enlarged fluid spaces in the brain, empty sella (a flattened pituitary gland region), and a low-lying spinal cord. Interestingly, these structural brain differences did not correlate with the presence of epilepsy or the severity of intellectual disability.16PubMed Central. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature That disconnect matters for families: finding something unexpected on a brain scan does not necessarily mean a worse outlook.
Heart, Hearing, and Other Organ Involvement
Congenital heart defects appear more often than once believed. After systematic cardiac screening of 46 genetically confirmed patients, heart defects were found in 38 percent of those with ANKRD11 point mutations. The most common were obstructions of the left ventricular outflow tract, followed by septal defects. A distinctive association with a specific type of defect called atrioventricular septal defect was identified and may serve as a diagnostic clue in young children.17PubMed. Congenital heart defects in molecularly confirmed KBG syndrome patients Patients with 16q24.3 deletions, rather than point mutations, may have a somewhat different cardiac profile, with septal defects appearing in a larger proportion.
Hearing loss, typically a mix of conductive and sensorineural types, is another recurring issue. It can be compounded by chronic middle-ear infections, which are frequent in young children with the syndrome.18PubMed. KBG syndrome in a cohort of Italian patients Because speech is already the most vulnerable developmental domain, even mild hearing loss can have outsized consequences. Baseline hearing screening at diagnosis and regular follow-up are considered important parts of management.19European Journal of Human Genetics. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients
An adult-focused survey of 91 individuals with KBG syndrome documented high rates of psychiatric conditions, sleep problems, gastrointestinal complaints, and ongoing dental and skeletal issues, alongside the cardiovascular and sensory problems already known from childhood studies.20PubMed Central. Life Beyond Childhood: Insight Into the Lived Experience of 91 Adults With KBG Syndrome Through an Online Patient/Caregiver-Reported Co-Produced Questionnaire This suggests that medical surveillance should not stop when patients age out of pediatric care.
Growth and Growth Hormone Treatment
Short stature is common in KBG syndrome. Height tends not to normalize with age, unlike weight and head circumference, which often drift toward typical ranges during adolescence. In a large European cohort, median adult height remained around 1.5 standard deviations below the population mean.21Human Molecular Genetics. Natural history of KBG syndrome in a large European cohort
Growth hormone therapy has been tried in a growing number of cases. The largest report to date included 18 treated patients and found that the median height improved from about 2.9 standard deviations below the mean before treatment to 1.8 standard deviations below at the latest measurement. Half the patients gained at least one full standard deviation, and over half of those who started below the normal range reached normal height.22PubMed. Growth Hormone Treatment in Patients With KBG Syndrome: Novel Insights, Challenges and Recommendations From Six New Patients and Literature Review An earlier, smaller report showed similar results: in ten treated children, nine showed height improvement, with no adverse effects reported during the first year.23PubMed Central. Growth hormone therapy for children with KBG syndrome: A case report and review of literature Interestingly, responses were comparable whether or not the child had documented growth hormone deficiency on lab testing, which means that a normal growth hormone level does not rule out benefit from treatment.24PubMed. Growth Hormone Treatment in Patients With KBG Syndrome: Novel Insights, Challenges and Recommendations From Six New Patients and Literature Review
Getting to a Diagnosis
KBG syndrome has historically been underdiagnosed. The facial features are subtle, the cognitive effects are often mild enough that a child enters school without a genetic workup, and the dental hallmark does not appear until permanent teeth come in. Many patients receive a diagnosis only after whole exome sequencing is performed for an unspecified developmental delay or unexplained seizures. In one case, a child with a complex movement disorder and developmental delay was diagnosed only after whole exome sequencing identified a frameshift mutation in ANKRD11, unifying what had seemed like separate problems under a single diagnosis.25PubMed Central. Case report of paroxysmal dystonia in a child with KBG syndrome: Expansion of the phenotype and utility of whole exome sequencing
The diagnostic landscape is shifting. Artificial intelligence-driven facial analysis tools are being explored as a way to flag possible cases before genetic testing, which could reduce the delay between first clinical concern and molecular confirmation.26European Journal of Human Genetics. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients For now, the practical message for parents and pediatricians is that any child with developmental delay, unusually large upper incisors, and even a few of the other associated features warrants a conversation with a geneticist.
Recommended Evaluations and Therapies
There is no single treatment for KBG syndrome, but a coordinated set of evaluations and interventions can make a meaningful difference. Current expert recommendations include:
- Early therapies: Physical, occupational, and speech therapy starting as early as possible, ideally at least once weekly based on family reports of benefit.
- Hearing screening: Baseline audiometry at diagnosis, with follow-up to catch conductive losses from chronic ear infections.
- Cardiac evaluation: Echocardiography at the time of diagnosis, given the higher-than-expected prevalence of heart defects.
- EEG monitoring: Baseline EEG upon diagnosis and regular neurological follow-up given the high seizure rate.
- Growth assessment: Monitoring of growth parameters with consideration of growth hormone therapy for those with significant short stature.
- Gastrointestinal attention: Evaluation for abdominal complaints including possible abdominal migraines, which appear to be more prevalent than previously recognized.
These recommendations draw on published expert guidance and are likely to be formalized further as patient registries grow.27European Journal of Human Genetics. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients
What Adulthood Looks Like
Until recently, almost all published literature focused on children. That is changing. A natural history study of a large European cohort tracked patients across age groups and found that weight and head circumference tended to normalize after childhood, but height remained below average into adulthood.28Human Molecular Genetics. Natural history of KBG syndrome in a large European cohort Persistent microcephaly was present in about 12 percent of patients over age 21. A separate physician-reported study described long-term neurodevelopmental outcomes, noting ongoing challenges with seizure management, psychiatric conditions, and the transition to adult living and working arrangements.29PubMed. Natural history of adults with KBG syndrome: A physician-reported experience
The adult survey of 91 individuals painted a detailed picture: psychiatric comorbidities including anxiety and depression were common, sleep disturbances were widespread, and gastrointestinal symptoms persisted well beyond childhood.30PubMed Central. Life Beyond Childhood: Insight Into the Lived Experience of 91 Adults With KBG Syndrome Through an Online Patient/Caregiver-Reported Co-Produced Questionnaire For families, this underscores the need to plan for adult medical care, mental health support, and appropriate levels of independence rather than assuming that concerns resolve after childhood.
Prenatal Detection
KBG syndrome can occasionally be suspected before birth, though prenatal diagnosis remains uncommon. In a series of 12 fetal cases, five had increased nuchal translucency on first-trimester ultrasound, while others showed subtle findings like mild ventriculomegaly or brain cysts later in pregnancy. Four pregnancies continued to term, and infants were confirmed with the typical KBG phenotype by 12 months of age.31PubMed. Prenatal Diagnosis of KBG Syndrome: Phenotypic and Genotypic Features of 12 Fetal Cases With the Disorder The first reported antenatal case was identified through chromosomal microarray after an amniocentesis performed for a different reason found a 16q24.3 deletion.32PubMed Central. The first antenatal diagnosis of KBG syndrome As exome sequencing becomes more widely available in prenatal settings, more cases will likely be caught before birth, giving families time to prepare and connect with specialists.
Olfactory Bulb Anomalies and Emerging Research
One of the more surprising recent findings involves the sense of smell. Researchers studying a mouse model of KBG syndrome noticed abnormalities in the olfactory bulbs, the brain structures responsible for processing smell. When they looked at MRI scans from human patients, they found the same thing: severely underdeveloped or absent olfactory bulbs, which in at least one case corresponded with clinically confirmed inability to smell.33PubMed Central. Olfactory bulb anomalies in KBG syndrome mouse model and patients Anosmia, or the inability to smell, is rarely tested for in children and would be essentially impossible to assess in a toddler, so it may be far more common in KBG syndrome than anyone has documented. This feature is not yet part of routine clinical checklists, but it illustrates how much of the syndrome’s full picture remains to be mapped. It also raises the practical question of whether affected individuals should be counseled about safety measures related to smell, such as ensuring they have working smoke detectors and gas leak alarms rather than relying on their own noses.
A separate line of research examining DNA methylation patterns found that both ANKRD11 point mutations and 16q24.3 microdeletions produce a shared epigenetic signature, meaning the way genes across the genome are chemically tagged is altered in a consistent, recognizable pattern.34Human Molecular Genetics. ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome This kind of epigenetic signature could eventually serve as a diagnostic tool for ambiguous cases, particularly when a genetic variant of uncertain significance is found and clinicians need additional confirmation.