KBG Syndrome

KBG syndrome is a rare genetic disorder that affects multiple body systems, characterized by distinctive facial features, unusually large front teeth, short stature, skeletal abnormalities, and developmental delays. Named after the initials of the first families diagnosed, this condition shows wide variation in how it affects individuals, even within the same family.

Table of contents

• Identification Codes and Synonyms
• What is KBG Syndrome?
• How Common is KBG Syndrome?
• Characteristic Features
• Genetic Causes
• Diagnosis and Testing
• How is KBG Syndrome Inherited?
• Management and Treatment
• Related Conditions

Identification Codes and Synonyms

10084411
C537015
Q87.8

Short stature-facial and skeletal anomalies-intellectual disability-macrodontia syndrome, ANKRD11-related disorder, Macrodontia, mental retardation, characteristic facies, short stature, and skeletal anomalies, Short stature, characteristic facies, macrodontia, mental retardation, and skeletal anomalies

What is KBG Syndrome?

KBG syndrome is a rare genetic disorder that affects several body systems. The name “KBG” comes from the surname initials of the first three families who were diagnosed with this condition in 1975^[1][6]. The disorder was first described as a new “malformation/retardation syndrome” that included developmental delays, short stature, distinctive facial features, and unusually large teeth^[6].

The condition is characterized by a typical facial dysmorphism (unusual facial features), macrodontia (unusually large teeth) of the permanent upper central incisors, short stature, skeletal abnormalities, developmental delay, and behavioral abnormalities^[4]. While originally described as an autosomal dominant condition (meaning one altered gene copy can cause the disorder), it was later confirmed through identification of mutations in a specific gene^[6].

How Common is KBG Syndrome?

KBG syndrome is a rare disorder. More than 150 cases have been reported in the medical literature, though experts believe there are likely more people with the condition who have not been recorded^[1][4]. The gene involved, ANKRD11, is one of the most frequently mutated genes in patients with neurodevelopmental disorders (conditions affecting brain development and function) diagnosed through whole exome sequencing^[4].

For unknown reasons, males are affected more often than females. Additionally, females typically have milder features of the condition^[6][11]. Doctors think the disorder is underdiagnosed because the signs and symptoms can be mild and may be attributed to other disorders^[1]. The condition is likely underreported due to incomplete recognition and very mild presentations in some individuals^[6].

Characteristic Features

Facial Features

Individuals with KBG syndrome often have distinctive facial features. A characteristic feature is unusually large upper front teeth, particularly the permanent upper central incisors^[1][2]. This feature, called macrodontia, is observed in about 80% of cases and is considered a hallmark of the condition^[4]. Additional dental findings may include missing teeth or fewer teeth than normal (oligo- or hypodontia), premature teeth loss in adults, and enamel hypoplasia (thin or defective tooth enamel)^[4].

Other distinctive facial features include a triangular face shape, a wide and short skull (brachycephaly), widely spaced eyes (hypertelorism), wide eyebrows that may grow together in the middle (synophrys), a prominent nasal bridge with a bulbous nose, a long space between the nose and upper lip (long philtrum), and a thin upper lip^[1][2][4]. The characteristic facial dysmorphism is prominent in about half of patients^[4].

Growth and Skeletal Features

Most affected individuals are shorter than average from birth^[1]. Height below the 10th percentile is observed in about two-thirds of cases^[4]. A common skeletal abnormality is slowed mineralization of bones, known as delayed bone age. For example, an affected 3-year-old child may have bones more typical of a child of 2 years old^[1].

Additional skeletal features may include abnormalities of the bones of the spine (vertebrae) and ribs, abnormalities of the bones of the hands or feet, unusually short or curved fifth (pinky) fingers (brachydactyly or clinodactyly), flat feet, a large anterior fontanelle (soft spot on a baby’s head) with delayed closure, and scoliosis (curved spine)^[1][2][4].

Developmental and Behavioral Features

Development of mental and movement abilities is typically delayed in KBG syndrome. Developmental delay includes delayed motor milestones and markedly delayed speech, and is almost always present in all patients^[4]. Most affected individuals learn to speak and walk later than normal and have mild to moderate intellectual disability (difficulties with learning and problem-solving)^[1].

Behavioral disturbances including hyperactivity, aggressiveness, attention deficit, and autism spectrum disorders are recognized as constant clinical features^[4]. Most people with this condition have neurodevelopmental disorders, such as hyperactivity, anxiety, or autism spectrum disorder, which is characterized by impaired communication and social interactions^[1].

Other Medical Features

Less common features include hearing loss (which can be conductive, mixed, or sensorineural), seizures, and heart defects^[1][2]. Affected individuals may have feeding difficulties, particularly in infancy, and brain malformations^[2]. Additional features that have been reported include recurrent otitis media (ear infections), palatal abnormalities (problems with the roof of the mouth), and precocious puberty (early puberty)^[4][10].

There is significant variability in the clinical findings, even between affected members of the same family^[2]. Individuals with deletions of genetic material at 16q24.3 involving the ANKRD11 gene have similar findings to those with point mutations, but also have a higher incidence of other findings such as brain anomalies, congenital heart defects, severe astigmatism, thrombocytopenia (low platelet count), and potentially autism spectrum disorder among other behavioral problems^[6][11].

Genetic Causes

KBG syndrome is caused by alterations affecting the ANKRD11 gene, which is located at position 16q24.3 on chromosome 16^[1][4]. The ANKRD11 gene provides instructions for making a protein that enables other proteins to interact with each other and helps control gene activity^[1]. The gene encodes ankyrin repeat domain-containing protein 11, which has been shown to be a crucial chromatin regulator (a molecule that controls how genetic information is accessed) that controls histone acetylation and gene expression during neural development^[4].

The ANKRD11 protein is found in nerve cells (neurons) in the brain. It plays a role in the proper development of the brain and may be involved in the ability of neurons to change and adapt over time (plasticity), which is important for learning and memory. ANKRD11 may function in other cells in the body and appears to be involved in normal bone development^[1].

Most of the ANKRD11 gene mutations involved in KBG syndrome are loss-of-function alterations, which include nonsense and frameshift variants and larger deletions. These lead to an abnormally short ANKRD11 protein, which likely has little or no function^[1][6][11]. Haploinsufficiency (having only one working copy of the gene instead of two) appears to be the mechanism that causes the condition^[6][11].

Reduction of this protein’s function is thought to underlie the signs and symptoms of the condition. Because ANKRD11 is thought to play an important role in neurons and brain development, researchers believe that a partial loss of its function may lead to developmental delay and intellectual disability in KBG syndrome. However, the mechanism is not fully known. It is also unclear how loss of ANKRD11 function leads to the skeletal features of the condition^[1].

Diagnosis and Testing

A diagnosis of KBG syndrome can often be made after a detailed clinical examination and patient history. However, due to its variable presentation, genetic testing can also provide helpful information and confirmation of the diagnosis^[3]. The diagnosis is based on clinical evaluation; there is no consensus on diagnostic criteria^[4].

The diagnosis of KBG syndrome is confirmed by detection of either a heterozygous pathogenic variant (a disease-causing change in one copy of the gene) in ANKRD11 or deletion of genetic material at 16q24.3 that includes ANKRD11^[2]. The diagnosis is established by cytogenetic and molecular studies including a-CGH (array-comparative genome hybridization), targeted sequencing, gene panel, whole exome or genome sequencing^[4].

While there are no formal diagnostic criteria, several have been proposed. A clinical diagnosis of KBG syndrome should be suspected in an individual with two or more major findings or one major finding with at least two minor findings. Major findings include macrodontia of permanent upper central incisors, developmental delay or mild/moderate intellectual disability or learning difficulty associated with behavioral issues, characteristic facial appearance, post-natal short stature, and a first-degree relative with KBG syndrome^[6][11].

How is KBG Syndrome Inherited?

KBG syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder^[1][4]. The pattern of inheritance is autosomal dominant, meaning that transmission follows this pattern^[4][8].

Both familial and de novo (new) cases have been reported. Many cases occur sporadically due to new mutations^[4][8]. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family^[1].

For deletions of 16q24.3, approximately 75% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner. For ANKRD11 sequence variants, approximately 66% of reported pathogenic variants are de novo and the remainder are inherited in an autosomal dominant manner^[2][7][15].

The syndrome displays inter- and intra-familial variability, meaning it can affect people differently even within the same family^[6][11]. Prenatal testing and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member^[2][7][15].

Management and Treatment

There is no cure for KBG syndrome, but management is symptom-based and often requires a multidisciplinary approach^[10]. Treatment focuses on managing the specific manifestations present in each individual.

Treatment Approaches

Specific treatments may include surgical corrections and/or speech therapy for palatal anomalies (abnormalities of the roof of the mouth), nasogastric tube feeding in infants with feeding difficulties, and pharmacologic treatment for gastroesophageal reflux disease^[2][7][15].

For ear and hearing issues, pressure-equalizing tubes and/or tonsillectomy/adenoidectomy may be recommended for chronic otitis media (persistent ear infections), and amplification devices should be considered for hearing loss^[2][7][15].

Growth hormone therapy may be considered for short stature, and medication to arrest puberty may be needed for premature pubertal development^[2][7][15]. Growth hormone therapy may be effective in patients with KBG syndrome presenting with significant prepubertal short stature, even in the absence of growth hormone deficiency^[9].

Standard treatment approaches are used for seizure disorder, undescended testis in males, congenital heart defects, eye problems (strabismus and refractive errors), and developmental disabilities^[2][7][15].

Monitoring and Prevention

Routine monitoring is recommended for hearing, vision, growth, pubertal status (in children who have not yet reached puberty), and cognitive development^[2][7][15].

At the time of diagnosis, recommendations include an echocardiogram (heart ultrasound), palatal assessment, hearing screens, dental assessment, screening for developmental delays, autism and behavioral anomalies, EEG (brain wave test), and assessment for feeding difficulties or failure to thrive. Additional assessments depend on individual presentation and symptoms^[10].

Ototoxic drugs (medications that can damage hearing) should be avoided because of the risk for hearing loss^[2][7][15].

Specialists and Support

Care may require involvement from multiple specialists including neurologist, neurosurgeon, ear/nose/throat specialist, cardiologist, gastroenterologist, pulmonologist, nephrologist, hematologist, immunologist, general surgeon, neurodevelopmental physician, psychologist/psychiatrist, endocrinologist, urologist, dentist/orthodontist, craniofacial specialist, sleep specialist, and ophthalmologist^[10].

Pregnancy management should be tailored to the specific features in the affected woman. For example, involvement of a cardiologist and maternal-fetal medicine physician is recommended for a pregnant woman with a history of a congenital heart defect, and control of seizures during pregnancy for those with a seizure disorder^[2][7][15].

Related Conditions

The differential diagnosis (other conditions that may look similar) includes Cornelia de Lange syndrome, cleidocranial dysplasia, Robinow syndrome, and 22q11.2 deletion syndrome^[4][8].