Synonyms of KBG Syndrome

 short stature, facial/skeletal anomalies-retardation-macrodontia

General Discussion
KBG syndrome is a rare genetic disorder characterized by short stature, dental abnormalities,
developmental abnormalities of the limbs, bones of the spine (vertebrae), extremities, and/or
underdevelopment of the bones of the skeleton. Abnormalities of the head and face (craniofacial
dysmorphism) may also be present. Most individuals have some degree of developmental delay
or intellectual disability. The level of intellectual disability is usually mild. The specific symptoms
may vary from one person to another. KBG syndrome is caused by a change (mutation) in
the ANKRD11 gene or a loss of genetic material (microdeletion) on chromosome 16q that
involves the ANKRD11 gene. Mutations of this gene can occur spontaneously with no family
history, or be inherited in an autosomal dominant manner. KBG syndrome is named after the
initials of the last names of the first three families identified with this disorder in the medical
literature in 1975.

Signs & Symptoms

Children with KBG syndrome may display characteristic physical abnormalities of the
head and face (craniofacial dysmorphism). The shape of the skull can be abnormal, with
a flat back of the head (brachycephaly). Characteristic facial features may include eyes
that appear widely spaced apart (hypertelorism) or crossed (strabismus); wide, bushy
eyebrows; thin, bow-shaped lips; and/or a triangularly-shaped face. There is typically a
full tip of the nose with upturned nostrils. Characteristic features may also include
abnormally large teeth (macrodontia). Macrodontia is particularly common in KBG
syndrome and often affects the two upper middle teeth (upper central incisors) and
sometimes other teeth as well. Affected individuals may also have jagged, crowded, or
misaligned teeth and/or unusually short, flattened, supporting bones or sockets of the
jaw (mandible) that house the teeth (alveolar ridges). Microcephaly has been described
in some children. Microcephaly is a condition in which the circumference of the head is
smaller than would be otherwise expected based on age and gender. However, most
children with KBG syndrome have a normal head size.
A child with KBG syndrome may also be of short stature, have speech and hearing
impairments, and/or have mild to moderate levels of intellectual disability. Children with
intellectual disability may experience delays in reaching developmental milestones.
Most children will only experience mild learning disabilities. Other children will not have
intellectual disability and have no issues with learning or thinking that are related to
KBG syndrome. Part of the adults with KBG syndrome can live independently, but other
adults with KBG need external help or live in assisted facilities.
Children experience recurrent ear infections (otitis media), which may contribute to
hearing loss.
Some children experience behavioral anomalies such as impulsivity or poor
concentration, sometimes with a diagnosis of attention deficit hyperactivity disorder
(ADHD), temper tantrums, anxiety or shyness, or compulsive and sometimes
aggressive behavior. Autism spectrum disorder or autistic traits can also be present in
children with KBG syndrome. The nature of the behavioral abnormalities is variable and
can be mild.
Some children have epilepsy, usually during childhood. The type of epilepsy can vary
from generalized or partial seizures that respond well to therapy, to more complex forms
of epilepsy that are difficult to treat. Some children also have EEG abnormalities without
signs of seizures. Sometimes MRI scans of the brain show abnormalities.
Affected children may have delayed bone age, which means that a child’s bones mature
at a slower rate. Other malformations of the bones can be present, such as spinal
abnormalities (abnormal vertebrae or ribs); the shortened middle portion of the thigh
bones (femoral neck); abnormally developed hip bones (hip dysplasia/Perthes disease);
and/or shortened, hollow finger bones (metacarpals).
In some children, associated features may include a sunken, pushed-in appearance of
the chest (pectus excavatum or “funnel chest”); a single deep crease across the palms
of the hands (simian crease); certain bones of the hands may be short (short tubular
bones of the hands), pinkies that are unusually short (brachydactyly) and/or that may be
stuck in a bent position (clinodactyly).
Less commonly, additional findings have been reported in some children including
congenital heart defects, defects affecting the roof of the mouth (palate), webbing or
fusion (syndactyly) of the middle toes, and a webbed, short neck. Some males may
have undescended testicles (cryptorchidism). Advanced puberty had been reported in
some children. Some infants have feeding difficulties or sleep difficulties.
Delayed closure of the ‘soft spots’ or fontanelles has also been reported. An infant’s
skull has seven bones and several joints called sutures. Sutures are made of tough,
elastic fibrous tissue and separate the bones from one another. Sutures meet up
(intersect) at two spots on the skull called fontanelles, which are better known as an
infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together
until around age two or later. The sutures normally remain flexible until this point. In
some infants, this fusion is delayed.

Causes
KBG syndrome is caused by either an alteration (mutation) in the ANKRD11 gene, or a
loss of genetic material from chromosome 16q that includes the ANKRD11 gene. Genes
provide instructions for creating proteins that play a critical role in many functions of the
body. When a mutation of a gene occurs, the protein product may be faulty, inefficient,
or absent. Depending upon the functions of the particular protein, this can affect many
organ systems of the body.
The ANKRD11 gene contains instructions for creating a protein that is active in nerve
cells (neurons). The exact role of this protein is not fully understood. When the
ANKRD11 is altered or missing, individuals cannot produce enough functional copies of
this protein. More research is necessary to determine how low levels of the protein
product of the ANKRD11 gene causes the symptoms of KBG syndrome.
KBG syndrome is inherited in an autosomal dominant pattern. Most genetic diseases
are determined by the status of the two copies of a gene, one received from the father
and one from the mother. Dominant genetic disorders occur when only a single copy of
an altered or missing gene is necessary to cause a particular disease. The affected
gene can be inherited from either parent or can be the result of a new, spontaneous
mutation (gene change) in the affected individual. This may be referred to as a “de
novo” change. The risk of passing the altered gene or missing chromosome segment
from an affected parent to an offspring is 50% for each pregnancy. The risk is the same
for males and females.

Affected Populations
KBG syndrome is a rare disorder that affects males and females. Currently, more than
150 cases have been reported in the medical literature. The disorder can go
undiagnosed or misdiagnosed, making it difficult to determining the true frequency of
KBG syndrome in the general population.

Related Disorders
Symptoms of the following disorders can be similar to those of KBG syndrome.
Comparisons may be useful for a differential diagnosis:
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth
(congenital). Associated symptoms and findings typically include delays in physical
development before and after birth (prenatal and postnatal growth retardation);
characteristic abnormalities of the head and facial (craniofacial) area, resulting in a
distinctive facial appearance; malformations of the hands and arms (upper limbs); and
mild to severe intellectual disability. Many infants and children with the disorder have an
unusually small, short head (microbrachycephaly); a prominent vertical groove between
the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils
(anteverted nares); and a protruding upper jaw (maxillary prognathism) with small chin
(micrognathia). Additional characteristic facial abnormalities may include thin,
downturned lips; low-set ears; arched, well-defined eyebrows that grow together across
the base of the nose (synophrys); an unusually low hairline on the forehead and the
back of the neck; and curly, unusually long eyelashes. Affected individuals may also
have distinctive malformations of the limbs, such as unusually small hands and feet,
inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain
toes. Less commonly, there may be absence of the forearms, hands, and fingers.
Infants with CdLS may also have feeding and breathing difficulties; an increased
susceptibility to respiratory infections; a low-pitched “growling” cry and low voice; heart
defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The
range and severity of associated symptoms and findings may be extremely variable
from person to person. (For more information, choose “Cornelia de Lange” as your
search term in the Rare Disease Database).
Filippi syndrome is a rare disorder characterized by an abnormally small head
(microcephaly), a broad nasal base, and/or an unusual facial appearance. Symptoms
may include various limb malformations such as webbed fingers and toes (syndactyly),
permanently bent fingers (clinodactyly), and/or a single deep crease across the palms of
the hands (simian crease). In males, the sexual organs may be underdeveloped and the
testes may fail to normally descend into the scrotum (cryptorchidism). Intellectual
disability and speech impairment may be mild to severe. This disorder is thought to be
inherited as an autosomal recessive trait. (For more information on this disorder, choose
“Filippi” as your search term in the Rare Disease Database.)
Kabuki syndrome is a rare, multisystem disorder characterized by multiple abnormalities
including distinctive facial features, growth delays, varying degrees of intellectual
disability, skeletal abnormalities, and short stature. A wide variety of additional
symptoms affecting multiple different organ systems can potentially occur. The specific
symptoms associated with Kabuki syndrome can vary greatly from one person to
another. To date, mutation in one of two genes leads to Kabuki syndrome. The first gene
is KMT2D (formerly MLL2) and the second gene, which accounts for fewer cases of
Kabuki syndrome, is KDM6A. Clinical genetic testing is available for both genes. Kabuki
syndrome was first reported in the medical literature in 1981 by Japanese physicians.
The disorder was originally called Kabuki-makeup syndrome because the facial features
of many affected children resembled the makeup used by actors in kabuki, a form of
Japanese theater. The term “makeup” has since been dropped and the preferred term
for the disorder is Kabuki syndrome. (For more information on this disorder, choose
“Kabuki” as your search term in the Rare Disease Database.)