Kabuki Syndrome is a rare genetic condition that is typically linked with low muscle tone, slow postnatal growth, delayed development and mild to moderate learning difficulties. People with Kabuki are more likely than most people to be affected by a number of medical conditions and show distinctive musculo-skeletal and facial features.

 

Kabuki Syndrome is thought to affect 1 in 32,000 people. However, since testing has been available for the associated MLL2 and KDM6A gene abnormalities, some geneticists say that incidence is on the increase.

 

Key features and common challenges

The five key defining features of Kabuki used in diagnosis are:

• Facial features, including long eyelids (giving almond shaped eyes); broad, arched, sparse eyebrows; a depressed tip of the nose and prominent, large or cupped ears

• Skeletal abnormalities, including an inward bending little finger (clinodactyly)

• Bumps on the fingertips (called persistent foetal fingertip pads – everyone has them as a foetus but they usually disappear before birth)

• Mild to moderate intellectual disability (although there in some cases the level of intellectual impairment is very low)

• Slow postnatal growth

 

Other common issues include:

• Low muscle tone (present in virtually all infants with Kabuki Syndrome)

• Joint laxity at all ages. In turn this can lead to frequent joint dislocations and joint pain, scoliosis and other issues. Hip dislocations may occur even if the neonatal hip check is normal

• Speech delay (seen in virtually all patients and exacerbated by the low muscle tone, any unusual mouth features and learning difficulties)

• Language delay and impaired understanding

• Feeding difficulties (some children with Kabuki need to be tube fed to maintain adequate nutrition)

• Gut problems including malformation, poor absorption and reflux

• Low blood sugars (especially post-natally, but sometimes also in childhood)

• A high risk of obesity from adolescence

• Premature breast development in girls (premature thelarche)

• A highly arched or sometimes cleft palette and / or missing or fused teeth

• Autistic features

• A poor attention span

• Heart and kidney / urinary tract abnormalities

• Epilepsy (seizures occur in 15-25% of patients) and central nervous system malformations

• Growth hormone deficiency

• Issues with immunity and autoimmune disease

• Hearing loss and other eye / ear problems

 

The list of linked problems and complications is long. However, luckily, not everyone has to contend with all the issues. It is very useful to know what they are though, to stand a chance of spotting problems early.

 

Dyscerne has produced a full description of possible issues and http://kabukisyndrome.com/content/management-kabuki-syndrome and some families have found this to be very useful during medical appointments, particularly to help specialists less experienced with Kabuki get up to speed quickly.

 

Importantly, most children and adults with Kabuki lead happy lives and achieve well. And while their development may have been delayed, in most cases parents say “they get there in their own time”. That said, most people with Kabuki Syndrome will benefit from Speech Therapy (to support speech and language development and help with any feeding difficulties), Occupational Therapy (to help with the development of fine motor and writing skills, and manage any sensory issues) and Physiotherapy (to help build muscle tone and support gross motor development), and the earlier this support can be accessed the better.

 

Children with Kabuki access a range of educational provision including mainstream school, special education and specialist resource bases, and some go on to higher education. Most adults live independently with some support.

 

What causes Kabuki?

Genetic conditions can be inherited or can be caused by a new mutation: a spontaneous error in genetic replication. This can be at chromosome level (as with Down’s Syndrome, for example) or gene level (as with Kabuki). Most cases of Kabuki syndrome result from a new mutation – that is they occur in people with no history of the disorder in their family. In a few cases, an affected person is believed to have inherited the mutation from one affected parent. Tests during pregnancy are now available when one parent is known to have the condition.

 

The genes that have so far been identified as involved in Kabuki Syndrome are epigenetic. This means that instead of directly controlling one or two features themselves, they control how a large number of other genes express themselves – and so how cells throughout the body are built in an ongoing way. This is why Kabuki usually affects such a wide range of organs and systems in the body.

The hopeful thing is that because the mutated Kabuki genes tell other cells what to do as they form all over the body during growth and development, there may one day be a therapeutic opportunity to stop new cells forming with the same problems - which could help people with Kabuki even past their very early years. Research into this is ongoing at the Institute of Genetic Medicine at John Hopkins University in America.

Read more here:

http://www.hopkinsmedicine.org/news/media/releases/drug_treats_inherited_form_of_intellectual_disability_in_mice, 

 

The following information was taken from "Management of Kabuki Syndrome: A Clinical Guideline"

Journal Of Human Genetics

Gene Reviews

National Library of Medicine (NLM)

Dr. Nathalie Hurley

 

Development and Behaviour

In their series of 62 affected individuals, Niikawa [1988] reported that intellectual disability, usually in the mild to moderate range, was a prime important feature, seen in 92%. As more individuals with this condition have been recognized and reported, however, some authors have suggested that as many as one sixth have normal intelligence. 

 

A more recent review in which authors excluded reports judged to be less diagnostically clear calculated an overall frequency of intellectual disability closer to the original estimate. Most individuals with KS are able to speak and ambulate. Rare individuals are non-ambulatory but able to speak; others are non-verbal with no significant motor impairment. In a 2005 report spoke of an average age to walk unassisted of 20 months with a range of 15 to 30 months in 15 individuals with Kabuki as grammatic construction are of particular difficulty for individuals with KS.

 

In 2005 a standardized neuropsychological test on 11 children and adolescents with Kabuki Syndrome with reported relative strengths in verbal and non verbal reasoning with relative weakness in visuospatial skills. Receptive language skills were also greatly superior to expressive skills in the study.

 

Growth and Feeding

Neonates with KS exhibit normal growth parameters. However postnatal growth issues are relatively common (35% - 81%). Microcephaly may or may not accompany short stature. Growth hormone deficiency has been reported but not common.Feeding difficulties are quite common (70%) however, severity is variable. Many individuals with KS have gastroesophageal reflux. Others require gastrostomy tube placement for poorly coordinated suck and swallow. Consequently, some infants with KS exhibit failure to thrive.

 

Autism is a rare but described finding. 1997 reported four males with variable cognitive abilities, three of whom had features within the autism spectrum ranging from pervasive developmental disorder to autistic-like to autistic disorder. It is not clear that autism is present as a level above that seen in the general population. As KS becomes more widely recognized , true incidence of social communicative difficulties will become apparent.

 

Neurological

Many children with KS are hypotonic (25%-89%). Significant joint laxity may be a contributing factor. As with other conditions in which hypotonia is a feature, this finding improves with time. Seizures are seen more frequently in KS (10%-39%) than in the general population. Good seizure control is generally achieved with medication. Although most people with Kabuki syndrome undergo a brain MRI scan for indications such as seizures and/or developmental delay, major structural brain anomalies are rare. Symptomatic Chiari I malformation, however, has been reported in multiple affected individuals.

 

Cardiovascular

Approximately 40%-50% of individuals with KS have congenital heart defects. Left-sided obstructive lesions, especially coarctation of the aorta, are common; interestingly, these lesions are rare in the general population. Septal defects are also common.

 

Ophthalmological 

Ocular findings occur in more than one third of individuals with Kabuki syndrome and include:

• Blue sclerae

• Strabismus

• Ptosis

• Coloboma

• Corneal abnormalities such as Peters anomaly

• Optic nerve hypoplasia

• Cataracts

• Duane anomaly

• Pigmentary retinopathy

• Marcus Gunn phenomenon

Severe visual impairment, however, is rare.

 

 

Ears and Hearing

Most individuals with KS have prominent and cup-shaped ears. Ear pits are also relatively common.From a medical standpoint, chronic otitis media is a major cause of morbidity, including conductive hearing loss. It is not clear, however, whether this finding is related to an underlying susceptibility to infection or to the craniofacial abnormalities, such as palatal insufficiency.Up to 40% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur.

Inner ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, aqueductal enlargement have been reported.

 

Glue Ear

Other names for this are middle ear effusion, middle ear fluid or otitis media with effusion.

 

How The Ear Works:Sound travels down the ear canal (outer ear) and vibrates the eardrum. This vibration is passed over an air-filled cavity (middle ear) by 3 small linked bones to a fluid filled organ (inner ear) where it is changed into electrical signals for the brain.

What Is Glue Ear? When a child has glue ear the inner ear is healthy and so the child has all the necessary organs for normal hearing. The glue is a sticky fluid substance which may build up in the middle ear and interfere with the vibration of the small bones. This reduces the sound before it gets to the inner ear. Sounds may be muffled and not get through.

 

What Causes Glue?

The tubes from the nose which allow air into the middle ear are very small in babies. As the child grows the tubes get bigger and drainage improves. Temporary clogging up with mucus is common with catarrh and ordinary colds. It usually improves over about 3-6 weeks and no medical treatment is necessary. Another reason why the tubes do not work well is that children often have large adenoids. This pad of tissue at the back of the nose increases in size up to the age of 5-6 years and then shrinks away naturally. In some children it can block the tubes to the middle ear. Some children have allergies to such things as dust mites, pollen, tobacco smoke and some foods. This can block the nose and lead to difficulties getting air into the middle ear.

 

Does Glue Ear Matter?

Often it causes no problems at all and goes away without any treatment.

Seven out of ten children experience an episode of glue ear before they are 7 years old. Only one in ten will need treatment. A child with glue ear who is not having any problems from it does not need treatment.The only justification for treatment is when each child is assessed as an individual. If hearing is affected so that the child is having difficulty learning to speak or having difficulty at school then active treatment may be offered. If the child is having repeated ear infections surgical treatment may be offered.

 

What Treatment is Available?

The wait and see approach is the best choice in most cases. During this time hearing and speech development needs monitoring. If there are problems contact your local children's Audiology Services.Surgical treatment consists of draining the glue through the ear drum and inserting a ventilation tube called a grommet in the ear drum. This allows the middle ear to dry out. The ear drum rejects the grommet after a while and it falls out with the wax. The time varies between a few weeks and a few years. The adenoids are usually removed at the same time (in children age over 3 years). This reduces the chance of fluid returning when the grommet comes out. The benefits are instantly improved hearing and less infections. The disadvantages are admission to hospital (although it may only be for the day) and a general anaesthetic (so the child is asleep). Most children can swim with grommets fitted.

 

What Alternatives Are There?

No medical treatment has a guaranteed effect. Some other forms of treatment claim success (such as homeopathy and cranial osteopathy) but many cases get better without treatment. No scientific study has proved the benefits of these treatments.The temporary fitting of hearing aids is sometimes considered. They may be required for several years. This is not necessarily an easy option, but is available in certain cases.

 

What Can I Do To Help?Protect the child from tobacco smoke.- Attract the child's attention when you talk to them. Speak directly face to face. Most children are excellent at lip readying whih they learn themselves.- Use a clear voice at a slightly raised level. Do not shout.- Cut down background noises (TV, radio, music.)- Stay close to the child when speaking. Do not walk away with your back to them.

CONTACT YOUR LOCAL AUDIOLOGY SERVICE FOR FURTHER HELP AND INFORMATION.

 

Craniofacial

Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be under-ascertained. Almost three quarters of affected individuals have a high-arched palate. As with all children with palatal abormalities, feeding difficulties, frequent otitis media, and speech difficulties are more common in this subset of affected individuals. A number of individuals with lower lip pits have been reported.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

• Large, prominent, or cupped ears

are considered part of the diagnostic criteria of KS, and therefore present in almost all individuals who have a clinical diagnosis of KS.

 

Dental

A number of different dental anomalies in individuals with KS have been noted. Hypodontia is most common, with missing lateral and central incisors as well as premolars. Abnormally shaped teeth, small teeth, widely-spaced teeth, andmalocclusion have also been described.

 

Genitourinary

Renal and urinary tract anomalies are seen in more than 25% of affected individuals. Common renal findings include anomalies of kidney position and ascent (single fused kidneys, crossed fused renal ectopia), ureteropelvic junction obstruction, duplication of the collecting system,and hydronephrosis. Hypospadias, cryptorchidism, and (more rarely) micropenis can occur in males.females can demonstrate hypoplastic labia .

 

Musculoskeletal

Joint hypermobility is seen in 50%-75% of individuals with KS. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As most conditions with joint laxity, this finding improves with age.

Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts).

Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of individuals with a clinical diagnosis of KS.

 

Immunologic

Immune dysfunction has been described, mostly in adolescent. In 2005  a test showed that 16 of 19 individuals with KS had some form of hypogammaglobulinemia. Low levels of serum IgA have been reported in association with idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and recurrent sinopulmonary infections.

 

MLL2 Gene

In 2010 scientists discovered genetic alterations that account for most cases of Kabuki syndrome. Instead of sequencing the entire human genome, the new approach sequences just the exome, the 1-2 percent of the human genome that contains protein-coding genes.researchers sequenced the exomes of 10 unrelated individuals with Kabuki syndrome. Beginning with the premise that Kabuki syndrome is caused by alterations in just a single gene, the researchers compared the exomes of the 10 patients to the human genome sequence to look for differences shared by the affected individuals. Initially, the researchers identified none.

 

The researchers then tested the hypothesis that Kabuki syndrome is more genetically heterogeneous than originally assumed, and that multiple genes could potentially cause the disorder. Looking for novel variants in genes that were shared among subsets of the 10 patients' exomes, they found novel, matching variants that were shared in three genes in nine of the patient's exomes, shared in six genes in at least eight exomes, and shared in 16 genes among seven exomes.

 

With no obvious way to rank these gene candidates, the researchers categorized each Kabuki case based on a subjective assessment of how well the patient matched the characteristics of Kabuki syndrome. They also looked in particular for variants in genes that led to a loss of function. The combined analysis pointed to gene called MLL2.

 

Normal allelic variants: MLL2 is 36.3 kb in size and comprises 54 exons. It encodes a protein with 5537 amino acids.

The researchers found novel variants which lead to a loss of function in the MLL2 gene in the four highest ranked cases, and in three of the remaining six cases. The variants were nonsense and frameshift mutations. The nonsense mutation substituted a single nucleotide (a molecule that links to form DNA) in the gene code, while the frameshift mutation resulted in a four nucleotide deletion in the gene.

 

Deletion of KDM6A

Like we know since 2010 the identification of MLL2 mutations as a primary cause of KS, such mutations have been identified in 56%-76% of affected individuals, suggesting that there maybe additional genes associated with KS. In 2011 three KS individuals with de novo pertial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. Although KDM6A escapes X inactivation, we found a skewed X inactivationn pattern, in which the deleted X chromosome was inactivated in the majority of the cells. This study identifies KDM6A mutations as another cause of KS and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes.

 

Differential Diagnosis

Disorders that have overlapping features with Kabuki Syndrome.

- CHARGE syndrome, particularly cleft palate, heart defects, coloboma, and growth issues. However, the typical facial features and prominent fingertip pads in KS are distinct from those in CHARGE syndrome. Mutations in CHD7 are causative; inheritance is autosomal dominant.

- 22q11 deletion syndrome, particularly cleft palate, congenital heart defects, and urinary tract anomalies. However, the different characteristic facial features seen in the two conditions should distinguish them.

- IRF6-related disorders (Van der Woude syndrome and popliteal pterygium syndrome).

- Branchiootorenal (BOR) syndrome, particularly ear pits, cupped ears, hearing loss, and renal anomalies. However, individuals with BOR syndrome have otherwise normal craniofacies, normal growth, and normal development. In BOR syndrome the common renal anomallies are renal hypoplasia and/or agenesis, while in KS renal anomalies commonly include hydronephrosis and malposition. Branchial cleft cysts maybe present in BOR but have not been reported in KS.

- Ehlers-Danlos syndrome, hypermobility type or larsen syndrome, particularly significantjoint hypermobility (including congenital hip dislocation and patellar dislocations) and blue sclerae. These conditions are not associated with major malformations involving other organ systems or typical minor anomalies seen in KS.

- X Chromosome anomalies and a variety of other chromosome anomalies, which can be present with similar facial features, congenital heart defects, and growth issues. These can easily be distinguished from KS by a chromosome analysis or chromosome microarray (CMA).

- Hardikar syndrome, particularly prolonged hyperbilirubinemia with cleft lip and palate. However, individuals with KS do not typically develop pigmentary retinopathy or sclerosing cholangitis, as seen in Hardikar syndrome.