Kabuki Stars

by Dr. Nathalie Hurley

Origins of Kabuki Syndrome (KS)
KS was first described in Japan in 1981, by two Japanese doctors: Dr Niikawa and Dr Kuroki. It was later described in Europe and America around 1990. Other names used for the syndrome are ‘Kabuki make-up syndrome’, KMS or Niikawa–Kuroki Syndrome. The term ‘Kabuki make-up syndrome’ was originally coined as the facial features of KS children are often similar to the make-up used in a form of Japanese theatre called Kabuki, but the ‘make-up’ part of the name was dropped as it was felt this could be potentially offensive to people with KS. It is a very rare paediatric congenital (ie. present from birth) condition which consists of multiple physical and developmental problems.

Occurrence of Kabuki
Kabuki syndrome is rare, estimated at 1 in 32,000 births. However, it is likely to be under-diagnosed since the number of medical professionals who are familiar with the syndrome is still small. Diagnosis is further complicated by the fact that the syndrome comprises of such a wide range of symptoms and clinical features. It is found equally in boys and girls and there is no significance to the order of birth (ie. it is not more likely to happen in your first child compared with your second, for example).

Basic Genetics
Every human has 23 pairs of chromosomes, including a pair of sex chromosomes. Each chromosome is an X-shape with two ‘short arms’ and two ‘long arms’ and consists of millions and millions of separate genes, which consist of DNA and make up who we are. Our genetic make-up is called our genotype and how these genes make us look are called our phenotype – for example, having the genes XX makes our genotype ‘female’ but different genes give us brown or blonde hair, and this is our phenotype. Any of these genes can be accidentally duplicated, moved or missed out during foetal development in the womb, and it is these errors which give rise to genetic syndromes such as Kabuki. Common genetic diseases include Down’s Syndrome, where people have three copies of chromosome 21, and cystic fibrosis where there is an abnormality of one of the genes on chromosome 7.

Kabuki Genetics
It is not known exactly what genetic abnormality causes Kabuki syndrome. It was thought that it might be caused by a deletion of a gene on chromosome 8, but further studies on this and people with KS have not been able to prove this is actually the case. For the great majority of children, chromosomal studies give normal results. Microscopic gene deletions or duplications are very difficult to find in the type of genetic studies done in practice at present.

Diagnosing Kabuki
There is no definitive test for diagnosing Kabuki and a geneticist is usually the person who makes the diagnosis. Diagnosis is based on the recognition of four out of five main characteristics, with the distinct facial features being the most important.

• Facial features: Long eyelids (palpebral fissures) with turning-out of the outer third of the lower eyelid, arched eyebrows with a thin outer half, prominent eyelashes, prominent and/or misshapen ears, and flattened nasal tip.
• Skeletal abnormalities: May include short fingers (brachydactyly), abnormally short bones (brachymesophalangy ) and turning in of the fifth finger (clinodactyly), as well as spinal anomalies including scoliosis (bending of the spine).
• Dermatoglyphic (palm and sole) abnormalities: Including persistent fingerpads.
• Intellectual disability: Usually mild to moderate (in 92% of people with KS).
• Postnatal short stature: This means babies can often grow reasonably well inside the womb, but only grow very slowly after birth (growth restriction).

Kabuki is a complex syndrome with many associated findings. Co-existing conditions support a diagnosis but are not absolutely necessary to be present. Here is a list of some of the more common traits.

• Floppiness/inability to hold own weight or sit up (hypotonia)
• Excessively flexible joints (hyperlax joints)
• Feeding difficulties
• Behavioural difficulties
• Recurrent infections (often ear infections)
• Hearing impaired and/or inner ear malformations
• Congenital heart defects
• Kidney/urinary tract abnormalities
• Other organ abnormalities (less common) – twisting of the large bowel (malrotation of the colon), malformed anus, abnormal relaxation of the diaphragm (eventration) or hernias
• Small mouth, small jaw (micrognathia), cleft or high arched palate
• Missing teeth, unusually shaped teeth and misaligned teeth
• Sudden weight gain during puberty years
• Early breast development and/or precocious (early) puberty
• Immunological abnormalities – may include low platelets causing a dark blotchy rash (ITP), haemolytic anaemia (where the red blood cells break themselves down) and growth hormone deficiency
• Seizures
  

Intellectual, Sensory and Behavioural
Most individuals with Kabuki have mild to moderate intellectual disability. A few have normal intelligence, most of whom have learning difficulties such as struggling with fine motor, speech skills, and having a good memory. Delay in speech and language acquisition is very common, and this can be made worse by physical abnormalities in the face and palate, as well as having low muscle tone and poor coordination.
Sensory issues include a need for oral stimulation (chewing on non-food items), abnormal reactions towards various sensations and stimuli, panic-like reactions to certain noises, and aversion to textures and/or smells of select foods.
Individuals with KS have a need for routine. They have a tendency to fixate on certain activities or thoughts. It appears they have excellent memories for face recognition, song lyrics, dates of events, and even things like shopping lists. They also often have distinct behavioural features – for example, 50% are described as being unusually sociable, 30% as engaging in only minimal interaction with others, 74% as liking routine and 87% as having a happy disposition. Anxiety, obsessive/compulsive traits and autistic-type behaviours are commonly observed and mild depression has been reported in young adults.

Growth
Infants usually have normal birth weight and length, however, most will develop failure to thrive and postnatal growth retardation during the first year of life. Poor sucking and swallowing, reflux, recurrent infections, heart defects, and low muscle tone may all be contributing factors. Although growth hormone levels are in the normal range for most children, a significant number have a partial or complete deficiency. Obesity seems to be a common problem during puberty years. The adult with Kabuki will be shorter than average – two or more standard deviations below the mean.

Hearing
Hearing loss is a common finding in Kabuki syndrome and can be of three basic types: conductive, sensorineural or mixed.
Conductive hearing loss occurs when sound is not conducted properly through the outer ear, middle ear, or both, such as in ear canal obstruction or in an ear infection. It is generally a mild to moderate impairment because sound can still be detected by the inner ear. Generally, with pure conductive hearing loss, the quality of hearing (speech discrimination) is good, as long as the sound is amplified loud enough to be easily heard. This type of hearing impairment can often be medically or surgically treated. It has a frequency ranging from 24% to 82% in people with KS.

Sensorineural hearing loss is due to the damage of the inner ear, the cochlea, or due to impairment of the auditory nerve. It can be mild, moderate, severe, or profound, to the point of total deafness. It is a permanent loss and it doesn’t only affect sound intensity such as the ability to hear faint sounds but also makes it more difficult for you to recognise complex sounds, to understand speech and to hear clearly. This type of hearing loss is rare in Kabuki syndrome.

Mixed hearing loss – In some cases, such as after complications from recurrent ear infections, a conductive hearing loss occurs in combination with damage of the inner ear or of the auditory nerve. When this occurs the hearing loss is referred to as a mixed hearing loss.

Immunity and Blood Disorders
Virtually all children are more susceptible to chest and/or ear infections in their early childhood years. It is unclear whether the infections are secondary to underlying immune deficiencies or related to physical face/throat/ear abnormalities.

Cardiac disorders
Approximately half the children diagnosed with KS will have a cardiovascular malformation. A wide range of conditions are reported, but the most common are coarctation of the aorta (where the main blood vessel carrying blood from the heart around the body is narrowed) and ‘hole in the heart’ (ventricular and atrial septal defects). These can give symptoms such as difficulty feeding, failing to grow properly and can sometimes be picked up on clinical examination by a doctor.

Neurological Disorders
Other than intellectual disability, the most common neurological conditions are hypotonia (low muscle tone), microcephaly (small head), and seizures. There does not appear to be any one type of seizure associated with KS. The age of onset can range from infancy to middle childhood.

Hormone and Genitourinary Disorders
Low blood sugar (hypoglycaemia) is usually a short-lived problem in infants, but it has also been reported in older children. Urinary tract infections can occur, sometimes due to structural abnormalities and possibly due to immune problems. Common kidney anomalies include dysplasia (abnormal size or shape), agenesis (where the kidney is not present), horseshoe kidney and ectopic (displaced) kidney. Ureter (the tube from the kidney to the bladder) abnormalities include obstruction, reflux, and duplication. Undescended testes, abnormal urethral anatomy (where the tube from the bladder exists the penis) and small penis have all been reported. A significant amount of girls have premature breast development and, rarely, premature onset of puberty. Growth hormone deficiency, an underactive thyroid gland and insulin-dependent diabetes are all rare findings in KS.

Gastrointestinal System
The most commonly reported problem by parents is diarrhoea and/or constipation. It is unclear what the contributing factors are. Much less common abnormalities include diaphragm hernias or abnormal relaxation, twisting of the intestines, and abnormalities with the anus or rectum.

Skin/nails
Individuals with Kabuki can have abnormalities with the nails, hair and skin. Nails can be absent, incompletely formed and fragile. Brittle hair, irregular hair diameter and increased body hair have been rarely reported. Skin can be very elastic and stretchy. Many parents report a rosy, dry appearance to their children’s cheeks for no apparent reason.

Common specialities who you are likely to be referred to:
Genetics – Diagnosis is usually done by a geneticist based on the medical history and presenting characteristics of the child. The geneticist can provide updated information regarding the genetic implications for the family, recent clinical findings, and advise parents of current genetic studies.
Cardiology – If a heart condition was not discovered at birth, it is advised that every child have an assessment done for possible heart abnormalities.
Ear, Nose and Throat (ENT) – Frequent ear infections, cleft or high arched palate, hearing loss, and inner ear malformations all require evaluation and continued care.
Audiology – There is an increased risk of hearing loss (conductive and sensorineural). Hearing should be thoroughly evaluated in early childhood and periodically thereafter.
Ophthalmology – Routine eye exams are recommended due to increased risk of squints, unusual eye movements, short sightedness and other defects.
Orthopaedics – Joint laxity, hip/kneecap dislocations, foot and walking issues, and skeletal anomalies such as scoliosis are frequent findings and will require orthopaedic care.
Dentistry – Missing, unusually shaped, widely spaced, crowding, and misalignment are common dental issues. Sensitivity to oral stimulus frequently prevents proper oral hygiene. Routine treatment from a paediatric dentist is recommended.
Urology – Due to an increased risk of urinary tract malformations, an abdominal ultrasound is recommended.

Further speciality referrals that may be required:
Immunology – Abnormal immunity test results, recurrent infections, and allergies should be evaluated by an immunologist.
Haematology – Autoimmune conditions such as ITP (low platelets/clotting cells), haemolytic anaemia (low red blood cells), and polycythaemia (high red blood cells) have been associated with Kabuki.
Endocrinology – Low blood sugar, growth hormone deficiency, underactive thyroid, precocious puberty and adolescent obesity are possible conditions.
Feeding and gastroenterology – Infant/childhood feeding difficulties (some requiring tube feeding) are common and may persist. Chronic constipation and/or diarrhoea are common. Sensitivity to oral stimulus frequently interferes with eating. Assistance to maintain adequate nutritional intake is often necessary.
Neurology – Seizures are the most common condition that requires care from a neurologist. Others that are much less commonly reported can include tethered spinal cord, small head (microcephaly) and other structural brain abnormalities.
Anaesthestics – Certain physical (structural) features associated with Kabuki could complicate the effects of anaesthesia. General low muscle tone, cardiac issues, and neurological problems should all be considerations prior to the risks of anaesthesia. Glucose monitoring during all surgeries is important for tube-fed children in case of undiagnosed low blood sugar.

Life Expectancy
There is no evidence to suggest that people with Kabuki syndrome have a shortened life expectancy. Most of the medical complications can be corrected with medication or surgery and knowledge about the syndrome will increase over time. The fact there are relatively few adults who have been diagnosed with Kabuki is probably due to the fact it was only first discovered in the 1980’s and therefore not diagnosed in people born before this time.