KBG syndrome

Alternate names

Short stature, characteristic facies, macrodontia, mental retardation, and skeletal anomalies

Definition

KBG syndrome is a rare condition characterized mainly by skeletal abnormalities, distinctive facial features, and intellectual disability. "KBG" represents the surname initials of the first families diagnosed with the disorder.

Epidemiology

KBG syndrome is a rare disorder that has been reported in more than 150 individuals in the medical literature, though there are likely more who have not been recorded in the literature. For unknown reasons, males are affected more often than females. Doctors think the disorder is underdiagnosed because the signs and symptoms can be mild and may be attributed to other disorders.

Cause

• KBG syndrome is caused by mutations in the ANKRD11 gene.
• The protein produced from this gene enables other proteins to interact with each other and helps control gene activity.
• 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.

Gene mutations

• Most of the ANKRD11 gene mutations involved in KBG syndrome lead to an abnormally short ANKRD11 protein, which likely has little or no function. 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 speculate 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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. 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.

Signs and symptoms

• Common signs and symptoms in individuals with this condition include unusual facial features, skeletal abnormalities, and intellectual disability.
• A characteristic feature of KBG syndrome is unusually large upper front teeth (macrodontia).
• Other distinctive facial features include a wide, short skull (brachycephaly), a triangular face shape, widely spaced eyes (hypertelorism), wide eyebrows that may grow together in the middle (synophrys), a prominent nasal bridge, a long space between the nose and upper lip (long philtrum), and a thin upper lip.
• A common skeletal abnormality in people with KBG syndrome is slowed mineralization of bones (delayed bone age); for example, an affected 3-year-old child may have bones more typical of a child of 2.
• In addition, affected individuals can have abnormalities of the bones of the spine (vertebrae) and ribs.
• They can also have abnormalities of the bones of the hands or feet, including unusually short or curved fifth (pinky) fingers (brachydactyly or clinodactyly, respectively) and flat feet (pes planus).
• Most affected individuals are shorter than average from birth.
• Development of mental and movement abilities is also delayed in KBG syndrome.
• Most affected individuals learn to speak and walk later than normal and have mild to moderate intellectual disability.
• Most people with this condition have behavioral or emotional problems, such as hyperactivity; anxiety; or autism spectrum disorder, which is characterized by impaired communication and social interactions.
• Less common features of KBG syndrome include hearing loss, seizures, and heart defects.

Diagnosis

KBG syndrome should be suspected in an individual with developmental delay / cognitive impairment or significant behavioral issues who has :.

• At least two of the findings highlighted by an asterisk (*); OR
• One finding highlighted by an asterisk and at least two additional findings.

1. Craniofacial features
2. Macrodontia (mesiodistal width of permanent central incisors ≥10 mm in males, ≥9.7 mm in females) (see Figure1), especially of the upper central incisors
3. Characteristic facial appearance
4. Conductive hearing loss and/or chronic/recurrent otitis media
5. Palatal abnormalities
6. Hair anomalies (e.g., low hairline, coarse hair)

1. Skeletal features
2. Costovertebral anomalies
3. Postnatal short stature (length and/or height <10th centile)
4. Delayed bone age (>2SD below mean)
5. Brachydactyly
6. Large anterior fontanelle with delayed closure
7. Scoliosis

1. Neurologic features
2. Learning difficulties of variable severity
3. EEG abnormalities with or without seizures

1. Family history
2. A first-degree relative with KBG syndrome
3. Feeding difficulties
4. Cryptorchidism in males

1. Establishing the Diagnosis
2. The diagnosis of KBG syndrome is established in a proband by detection of either a heterozygous pathogenic variant in ANKRD11 or deletion of 16q24.3 that includes ANKRD11.

Treatment

Surgical corrections and/or speech therapy for palatal anomalies Nasogastric tube feeding in infants Pharmacologic treatment for gastroesophageal reflux disease Pressure-equalizing tubes and/or tonsillectomy/adenoidectomy for chronic otitis media Consideration of amplification for hearing loss Consideration of growth hormone therapy for short stature and medication to arrest puberty for premature pubertal development Standard treatment of seizure disorder, undescended testis in males, congenital heart defects, strabismus / refractive errors, and developmental disabilities.[1].

NIH genetic and rare disease info

• NIH info on KBG syndrome

KBG syndrome is a rare disease.

KBG syndrome Resources
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