Peer Reviewed Journal of Forensic & Genetic Sciences
Review Article(ISSN: 2638-6062)
Kabuki Syndrome: Current Understanding of Symptoms
and Treatment Strategies Volume 5 - Issue 1
Yalda Zhoulideh*
Graduated with master’s degree in Genetics at Islamic Azad University of Tabriz, Genetic Researcher, Tehran, Iran
Received: May 29, 2023; Published:June 07, 2023
*Corresponding author: Yalda Zhoulideh, Graduated with master’s degree in Genetics at Islamic Azad University of Tabriz, Genetic
Researcher, Tehran, Iran
Kabuki syndrome can be mentioned as one of the most severe and, at the same time, rare genetic abnormalities. The inheritance
pattern of this disorder can be an autosomal dominant or X-linked pattern. In this disease, KMT2D AND KDM6A genes are disrupted,
which encode histone methyltransferase and histone demethylase, respectively. The severity of the disease and associated signs and
symptoms can vary widely but may include distinct facial features, developmental delay, intellectual disability, and limb deformities.
Kabuki syndrome treatment may vary based on the specific symptoms that appear in each individual. This review will examine the
genes involved in this disease, phenotype, clinical manifestations, ways of diagnosis, and treatment of this disease.
Kabuki syndrome (KS: OMIM 147920) is a rare genetic disorder
that has two inheritance patterns: X-linked (associated with the
KDM6A gene) and autosomal dominant (associated with the
KMT2D gene). Other names for this disease include Kabuki-makeup
syndrome (KMS) and Niikawa-Kuroki syndrome. The reason for the
name of this disease is the appearance of the face of affected people
with the type of make-up of the actors of the traditional Kabuki
show in Japan [1-6]. For the first time, this disease was defined and
identified in 1981 by two groups of researchers, led by Dr. Norio
Nikawa, a Japanese geneticist, and Yoshikazu Kuroki, a Japanese
physician. Kabuki syndrome affects women and men in the same
proportion and does not increase among certain ethnic groups.
Also, its frequency can be considered as one in 32,000 live births.
However, since this disease includes a wide range of mild to severe
symptoms, some cases of the mild disease may never be detected,
and as a result, the number of cases is higher than the estimated
amount [7-10].
This heterogeneous disease causes very different symptoms in
affected people and varies from person to person. The severity of
the disease and associated signs and symptoms can vary widely;
still, they may include distinctive facial features, Permanent pads
between the fingers, hypermobility of the joints, sensorineural
deafness, diaphragmatic hernia, arched eyebrows, and elongated
eyelids [11-14]. This disease overlaps with some diseases, such as
CHARGE syndrome, Turner syndrome, Van der Woude syndrome,
22q11 deletion syndrome, and other disorders. Therefore, the
accurate diagnosis of this disease is both a challenging and vital
task because the subsequent treatments and measures to improve
the physical condition and the spirit of the patient and his family
depend on the correct diagnosis. Since this disease can endanger
the affected person’s life in severe cases, it is imperative to start
treatment early. Also, genetic counseling for family members is
one of the most fundamental approaches to prevent more cases.
Considering the importance of genetic disorders and their spread
in some societies, we reviewed Kabuki syndrome, its disease
mechanism, diagnosis, and other related issues.
Set1-like H3K4 HMTs consists of six subsets including KMT2A,
KMT2B, KMT2C, KMT2F, KMT2G, and KMT2D. KMT2D (Histonelysine
N-methyltransferase 2D) is a critical histone H3 lysine 4
mono-methyltransferase in mammals [15,16]. The other name of
this gene is MLL2, which plays an essential role in the embryo’s
development and suppressing tumors. A loss of function mutation
in the KMT2D gene can cause Kabuki syndrome. Other diseases that
can occur due to disruption in this gene include congenital heart
disease and some types of cancer, such as pheochromocytoma, non-
Hodgkin lymphomas, pancreatic cancer, and prostate cancer [17-
26]. An enzyme called methyltransferase, produced by the KMT2D
gene changes histones by adding a methyl group. KMT2D, which
has been altered, is inoperable. As a result, histone lysine-specific
methylation is disturbed [27-33]. This gene is located in the long
arm of chromosome 12. KMT2D gene produces a protein with the
same name, which has different domains. In the C-Terminal, there is
a SET domain that regulates methyltransferase activity, then FYRC
and FYRN domains, and then PHD and HMG-I domains. On the
N-Terminal side, there are six PHD domains [34-48]. The structure
of the KMTD2 protein is shown in Figure 1.
KDM6A (Lysine-specific demethylase 6A) belongs to the
2-oxoglutarate (2OG)-dependent dioxygenase family, which is a
protein-coding gene whose protein product plays a role in normal
development and tumor suppression. Another name for this gene is
UTX, located in Xp11.3 and causes random inactivation of one of the
X chromosomes [49,50]. Its mutation can cause various diseases
such as Kabuki syndrome and cancers such as multiple myeloma,
breast, and colon. A methyl group from lysine is removed by the KDM6A gene product, an enzyme that demethylates histones.
KDM6A with a mutation cannot function, and developmental
abnormalities result from the disruption of histone lysine-specific
demethylation. The protein product of the KDM6A gene has six
domains on the N-Terminal side called tetratricopeptide repeat
(TPR) and one on the C-Terminal side called Jumonji C (JmjC) that
play a role in regulating demethylation [51-54]. The structure of the
KDM6A protein is shown in Figure 2.
The symptoms of Kabuki syndrome overlap with various
diseases such as CHARGE syndrome, Turner syndrome, Van der
Woude syndrome, 22q11 deletion syndrome, and other disorders
[55-65]. However, the clinical symptoms of this disease can be
generally categorized as follows:
Facial Features
About one-third of patients have also been reported to have
mid-face hypoplasia, hypodontia, cleft palate, and a trapezoidal
philtrum. Over 40% of people with KS have dental anomalies.
Other signs and symptoms that can be seen in almost all affected
individuals include persistently drooping eyelids, arched eyebrows,
a sunken tip to the nose, a long eyelid furrow, long eyelashes, a
small chin, and a wide nose [66-71]. Figure 3 shows a picture of a
person with Kabuki syndrome.
Figure 3: Image related to Kabuki syndrome facial features. Note the wide nose with a flat tip, downward cleft eyelids, and
arched eyebrows. (Note: out of respect for patients’ rights, this image is not related to a natural person and is designed by the
software).
Features of hearing
15 to 25 percent of patients have hearing and ear issues. Some of
the most typical otolaryngologic findings in KS include dysmorphic
pinnae, large, cup-shaped ears, otitis media, and hearing loss. It
seems that otitis media is expected [72,73].
Characteristics of the Reproductive and Urinary System
Over 30% of KS patients have some form of renal abnormalities,
such as hydronephrosis, renal hypoplasia or dysplasia, or kidney
fusion defects, such as the horseshoe kidney, like CHARGE
syndrome. Patients with kidneys that were noticeably dysplastic
required transplantation. About 31% of cases have been reported
to have hypospadias, small penis, and cryptorchidism [74-78].
Developmental Delay
Patients with KS appear to experience specific delays in
language and speech maturation, and these delays or absences may
be present in KS patients. During the first year of life, most patients
experience failure to thrive and postnatal growth retardation.
Although they eat a healthy diet, these individuals may not grow to
their full height and have excessive obesity [79-85]
Eye Features
About 35 to 60 percent of patients with KS have ophthalmologic
abnormalities. Strabismus and blue sclerae are among the most
typical findings. Refractive errors, cataracts, delayed visual
maturation, optic nerve hypoplasia, ptosis, nystagmus, palsy of
the third cranial nerve, and Marcus Gunn’s phenomenon are less
frequent findings [86-88].
Heart Problems
The prevalence of congenital heart defects in this population
has been estimated to be between 40 and 50 percent, and many
different congenital heart defects have been described in patients
with KS. Juxta ductal coarctation of the aorta, a relatively uncommon
heart defect, appears to be the most frequent finding, followed by
VSD and ASD. Males seem to experience coarctation of the aorta in
KS much more frequently than females [89-91].
Digestive Problems
While malrotation of the intestines has been documented in a
few patients with KS, gastrointestinal abnormalities are uncommon,
occurring in only about 7% of cases. Instead, most patients with
KS have abnormalities of the anus or rectum, such as anal atresia,
anovestibular fistulas, or anteriorly placed anuses. Additionally,
biliary atresia and neonatal sclerosing cholangitis that required a
liver transplant have been documented [92-95].
Abnormalities related to the Brain
Autism or behaviors resembling autism have been identified
in several patients. 90% of affected patients exhibit mild to severe
mental retardation, and in most cases, their IQ level is below 85. Only
10% of affected patients have average intelligence. Seizures occur
in 15 to 40% of KS patients. A large arachnoid cyst, polymicrogyria,
non-specific cerebral atrophy or enlarged ventricles, and significant
brain structural abnormalities have all been seen in MRI studies of
KS patients [96-100].
Skeletal Abnormalities
In KS, skeletal abnormalities are frequent. Other abnormalities
include the sagittal cleft, short fifth digits with short fifth
metacarpals, cone-shaped proximal second through fifth phalange
epiphyses, coronal synostosis, dislocation of the hip joints, and
various vertebral anomalies [101-107].
For prenatal diagnosis of patients with KS, the ultrasound
method can detect some abnormalities, such as the lack of proper
development of fingers or toes, twisting of the intestine, facial
abnormalities, and other features. Individuals with specific
morphological features associated with KS may be candidates for
genetic testing for KMT2D and KDM6A genes at birth [108]. In
addition, sometimes, the symptoms of the disease are minimal,
and NGS can be done to be sure. Currently, there are no consensus
diagnostic criteria for KS; however, five principal components can be
used for the early diagnosis of KS, including skeletal abnormalities,
specific facial features, mental retardation, developmental delay,
and interdigital pads.
Kabuki disease can present various phenotypes and
complications depending on the mutated gene and the general
conditions. The proposed treatment depends on the phenotype
and the affected organ because not all individuals with this disease
exhibit the same symptoms. In addition, there is no universally
effective cure for this illness [109,110]. All available treatments
have aimed to improve patients’ quality of life because there is
currently no proven standard treatment for this illness. Genetic
counseling is one of the most crucial recommendations to Kabuki
patients and their family because it can aid in more effective and
better disease management. Since this patient exhibits symptoms
almost from birth, medical monitoring is required to prevent severe
complications of the disease because, occasionally, some of the
complexities of this condition can endanger a person’s life. For kids
with Kabuki, pediatricians are frequently the first point of contact
for medical attention. The psychology of illness should be one of the
key topics covered during treatment. People close to the affected
person or in charge of their care may experience emotional stress.
For these people to live peaceful daily lives with their ill loved ones,
psychological counseling is helpful. Cognitive difficulties can be
one of the signs of Kabuki. Although not all affected patients have
this disease, it is better to educate those who do so that they can
safeguard their health from the disease’s emergency.
KMT2D and KDM6A genes contribute to the complex genetic
condition known as Kabuki. It appears that more tests should
be considered to find additional causes of this disease and that
genome sequencing can be helpful. However, some genes effective
in causing the disease to remain unknown. Furthermore, there is no
known cure for this illness, and all current therapies mainly serve
as supportive care. CRISPR/Cas9 and gene therapy research may
someday result in the ability to treat this genetic condition.
The author declares that the research was conducted without
any commercial or financial relationships that could be construed
as a potential conflict of interest.