Kabuki syndrome is a very rare genetic disorder that develops due to both sporadic and familial mutations of KMT2D and KDM6A genes. The clinical presentation is distinguished by unique facial features, impairment of growth and intellectual capacities, changes in the skeletal system, and dermatoglyphic abnormalities. The diagnosis is difficult to make in the absence of a thorough clinical assessment, meaning that a patient history coupled with a physical examination is crucial for raising suspicion. Genetic testing is used for confirmation.
Kabuki syndrome is a rare phenomenon in clinical practice, but several distinct features distinguish this syndrome from an array of disorders presenting with similar signs and symptoms    :
- Facial changes - Virtually all patients suffering from Kabuki syndrome have large, cupped ears, very broad and arched eyebrows, elongated palpebral fissures that are often accompanied by eversion of the lower lid (particularly the lateral third), and a depressed nasal tip  .
- Intellectual disability - Present in up to 92% of patients, intellectual impairment is an important manifestation of Kabuki syndrome  . Many patients often have a delayed development of speech along with difficulties in cognition and understanding of words  .
- Growth deficiency - Despite having a normal height at birth, postnatal growth retardation is reported in a significant percentage of cases   .
- Skeletal anomalies - Malformation of the spinal column (scoliosis, vertebral deformities), a cleft hand, brachydactyly, a shortened fifth finger of the hand, and underdeveloped ribs are notable disorders of the skeletal system   .
- Skin - persistent fetal finger pads and abnormal dermatoglyphic patterns are hallmarks of Kabuki syndrome    .
In addition to these five crucial types of changes, other manifestations may stem from the cardiovascular system (mainly in the form of congenital heart disease such as coarctation of the aorta, atrial septal defects, and ventricular septal defects), gastrointestinal system (anal atresia), the eye (ptosis, strabismus), and the oral cavity (hypodontia and widely spaced teeth)    . Furthermore, hearing loss, predisposition to infections and autoimmune diseases, and feeding issues are also noted    .
Entire Body System
- Short Stature
These investigators described a group of patients sharing typical facial features, skeletal anomalies, mental retardation, short stature, and dermatoglyphic anomalies. [ncbi.nlm.nih.gov]
- Developmental Delay
Kabuki syndrome is a rare genetic disorder characterized by congenital anomalies and developmental delay. It is often associated with impaired immune response and autoimmune abnormalities. [ncbi.nlm.nih.gov]
- Feeding Difficulties
Facial dysmorphisms (94%), feeding difficulties (100%) and hypotonia (100%) suggested the clinical diagnosis of KS. No significative differences in terms of facial features were noticed between mutation positive and negative patients of the cohort. [ncbi.nlm.nih.gov]
We believe that KS is a newly recognized cause of syndromic CHI and that this diagnostic should be envision in CHI patients presenting with feeding difficulties, mental retardation, malformations and/or facial dysmorphism. [ashg.org]
difficulty (infants), obesity (adulthood), short stature, poor sleep, hyperinsulinemia (hypoglycemia), epilepsy, cardiac defects (e.g. coarctation of the aorta), vertebral anamolies (e.g. butterfly vertebrae), sparse lateral eyelash, finger anomaly [en.wikipedia.org]
The disorder affects males and females, and can affect different organs and cause a variety of problems that our team is able to treat and address, including: Growth deficiency Feeding difficulties Low muscle tone in early years Seizures Hearing issues [kennedykrieger.org]
- Recurrent Bacterial Infection
His clinical course consisted of numerous hospitalizations for recurrent bacterial infections and congenital hypogammaglobulinemia characterized by low serum IgG and IgA but normal IgM levels, and decreased antibody levels to immunizations. [ncbi.nlm.nih.gov]
- Failure to Thrive
Infants and young children often experience difficulties relating to hypotonia, feeding issues/failure to thrive, infections, surgical repair of heart and palate defects and developmental delays. [senteacher.org]
If the stature is normal at birth, neonates soon present with growth delay and frequent failure to thrive of variable severity. Microcephaly is inconstant. [orpha.net]
Jaw & Teeth
Liver, Gall & Pancreas
The proposita had arched eyebrows, long and upward slanting palpebral fissures, cleft lip and palate, retromicrognathia, brachydactyly of hands and feet, stubby fingers, nail hypoplasia, and prominent finger pads. [ncbi.nlm.nih.gov]
Musculo-skeletal anomalies include brachydactyly V, brachymesophalangy, clinodactyly of fifth digits, spine abnormalities and joint hypermobility and dislocations. [orpha.net]
Skeletal abnormalities: may include brachydactyly (shortness of fingers), brachymesophalangy (abnormal shortness of bone) and clindactyly (turning aside) of the fifth finger, and vertebral anomalies including scoliosis. [pdkselayang.blogspot.com]
- Joint Dislocation
Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. [ncbi.nlm.nih.gov]
This strengthens muscle tone and lessens the chance of joint dislocations. Occupational therapy helps develop coordination and fine-motor skills. Speech therapy. [hcpro.com]
In general, those with a KMT2D mutation are also more likely to have renal anomalies, feeding problems, premature thelarche in females, joint dislocations, and palatal anomalies than are those without a KMT2D mutation. [flipper.diff.org]
The hypermobility type of Ehlers-Danlos syndrome resembles KS in that patients with both conditions can have loose/lax joints, joint dislocations, and blue sclerae. [forgottendiseases.org]
However, as children enter adolescents, they have a tendency to gain too much weight, which can make other health problems (such as joint dislocations) worse. [rarediseases.org]
- Muscle Hypotonia
This two-year old boy was referred to our hospital at 3-months of age for his growth retardation and muscle hypotonia. Because of his peculiar face, brachydactyly V and fingertip pad, we diagnosed him as having Kabuki syndrome. [ncbi.nlm.nih.gov]
- Hearing Impairment
Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. [ncbi.nlm.nih.gov]
Patients can also develop heart defects, urinary tract problems, abnormal dentition, hearing impairments, early puberty, seizures, and recurrent infections. [pdkselayang.blogspot.com]
impairment Conductive deafness Conductive hearing loss [ more ] 0000405 Failure to thrive Faltering weight Weight faltering [ more ] 0001508 Feeding difficulties Feeding problems Poor feeding [ more ] 0011968 High palate Elevated palate Increased palatal [rarediseases.info.nih.gov]
Rena Ellen Falk and Arti Pandya, Hereditary Hearing Impairment, Emery and Rimoin's Principles and Practice of Medical Genetics, 10.1016/B978-0-12-383834-6.00150-6, (1-38), (2013). [doi.org]
- Broad Eyebrows
Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella [ncbi.nlm.nih.gov]
(The typical facial features: elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears) Dental. [flipper.diff.org]
Cranio-facial features include elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying sparseness or notching; short columella with depressed nasal tip; large, prominent [orpha.net]
Patients often have long palpebral fissures with eversion of the lateral one-third of the lower eyelids and arched and broad eyebrows that resemble the make-up of actors in Kabuki, the traditional Japanese play. [genome.jp]
Because the diagnosis is primarily based on clinical criteria (but also because the disorder could be life-threatening in the absence of early recognition, particularly if congenital heart disease is present), a thorough clinical assessment is vital. The physician must take a detailed patient history during which the onset of symptoms and signs and their progression should be evaluated. Some studies have established the autosomal dominant pattern of inheritance in a significant number of patients meaning that a family history might provide important clues to the diagnosis  . The majority of signs can be detected at the physical examination, but certain imaging studies may be necessary. As congenital heart diseases are often present , cardiac ultrasonography is a useful study. Once solid evidence is raised through clinical findings, genetic studies should be sought. Many patients develop Kabuki syndrome without a familial component (through de novo mutations)  . The analysis of two genes - KMT2D (involved in the autosomal dominant form) and KDM6A (responsible for sporadic forms) will confirm the diagnosis      .
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- Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–793.