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Diagnosis and Treatment

Diagnostic Criteria

The clinical features in KS are highly variable between individuals with the syndrome [1]. Until recently, the diagnosis of Kabuki syndrome (KS) is primarily established on the basis of clinical findings [2]. These may include signs and symptoms that patients present with. Consensus diagnostic criteria for KS have not been firmly established [2]. Recently, however, efforts have been made to include mutation screening as part of the diagnostic process [1].

Clinical Findings

From a clinical perspective, researchers have defined five cardinal manifestations to facilitate the initial diagnostic process of KS [3]. These include:

  1. Peculiar characteristic facial features
  2. Skeletal anomalies
  3. Dermatoglyphic abnormalities
  4. Mild to moderate intellectual disability
  5. Postnatal growth retardation

A more detailed description of these clinical features of KS is available in Symptoms and Symptom Management.

Molecular Screening

From a molecular perspective, KS is believed to be genetically heterogeneous with a spectrum of genetic mutations in MLL2 (MIM 602113; NM_003482), the major causative gene for KS [1]. Mutations in MLL2 have been found in 56% yo 75% of patients [4]. In patients without a mutation in MLL2, researchers have identified heterozygous deletions in a second gene for KS, KDM6A (UXT, MIM 300128) [5].  A more thorough discussion of the molecular findings in KS is available in Research.

With this molecular knowledge, researchers have added sequence analysis of MLL2 as a standard molecular genetic screening in patients with suspected KS [1]. In patients who did not show a MLL2 mutation, array-comparative genomic hybridization (array-CGH) should prove a useful screening algorithm to help establish a differential diagnosis molecularly [1,5].

References

  1. Bögershausen N, Wollnik B. Unmasking kabuki syndrome. Clin Genet 2012, Nov 6.
  2. Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2004: 67: 209-219.
  3. Matsumoto N, Niikawa N. Kabuki make-up syndrome: A review. Am J Med Genet C Semin Med Genet 2003, Feb 15;117C(1):57-65.
  4. Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, et al. MLL2 mutation spectrum in 45 patients with kabuki syndrome. Hum Mutat 2011, Feb;32(2):E2018-25.
  5. Lederer D, Grisart B, Digilio M, Benoit V, Crespin M, Ghariani S, & … Verellen-Dumoulin C. (2012). Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Of Hum Genet, 90(1), 119-124.

Differential Diagnosis

Some disorders share overlapping features with KS [1]. Evaluation of the patient via clinical interview and assessment as well as chromosome analysis is often performed to investigate the causes of clinical findings, such as typical facial features and various congenital defects that are characteristic of KS, but may also appear in other genetic syndromes [2].

Chromosome anomalies on the X chromosome and on chromosome 8 can give rise to symptoms and test results very similar to that of KS.

Turner Syndrome

Some clinical characteristics of KS appear to overlap those of Turner syndrome (TS) [4]. Symptoms overlapping with those seen in KS may include heart defects, short stature, scoliosis, and similar facial features.

22q11 Deletion Syndrome

Children with 22q11 deletion syndrome (Synonyms:  velocardiofacial syndrome, DiGeorge syndrome, CATCH 22) may present with clinical features, such as cleft palate, cardiac malformations, and renal anomalies, all of which can also occur in KS [3]. However, the etiology and pathogenesis of this genetic syndrome are not shared by those found in KS.

Noonan Syndrome

Noonan syndrome involves a complex of symptoms [8], such as congenital heard defects, short stature, feeding difficulties, delay in motor development, and distinctive facial features (philtrum, widely spaced eyes, low-set ears that appear rotated backward) as well as characteristic physical appearance (short neck, sunken/protruding chest, scoliosis) [7].

Hardikar Syndrome

Hardikar syndrome comprises of a combination of obstructive liver disease, cleft lip, cleft palate, long palpebral fissures, eye and urogenital abnormalities [9]. Prolonged hyperbilirubinemia with cleft lip/palate, growth retardation, feeding difficulties,  are feature commonly seen in both KS and Hardikar syndrome [1,6]. However, symptoms such as pigmentary retinopathy or sclerosing cholangitis are not usually seen in individuals with KS.

Charge Syndrome

Individuals with CHARGE syndrome also share some of the same clinical features with KS patients. These include birth defects, such as cleft palate, cardiac malformations, coloboma, and growth retardation. However, typical KS facies and prominent fingertip pads in KS are not seen in Charge syndrome.

van de Woude’s syndrome

van de Woude’s syndrome (VWS) is a genetic condition that result from abnormalities in the development of the face. Children with VWS may present with some of the KS-like facial features, such as cleft lip/palate, lip pits, and hypodontia [3].  However, these individuals do not show symptoms of atypical growth and development, cardiac malformations, or the typical KS facies.

References

  1. GeneReviews™ [Internet]. Kabuki Syndrome — NCBI Bookshelf;  Available from:  http://www.ncbi.nlm.nih.gov/books/NBK62111. Accessed 22 Feb 2012.
  2. The Swedish Information Centre for Rare Diseases. Kabuki Syndrome — Rare Diseases. Available from:  http://www.socialstyrelsen.se/rarediseases/kabukisyndrome. Accessed 27 Feb 2012.
  3. Adam MP, Hudgins L. Kabuki syndrome: A review. Clin Genet 2005, Mar;67(3):209-19.
  4. Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J of Med Genet Part C (Semin Med Genet) 117C: 57-65.
  5. Salpietro DC, Guarneri F, Rigoli L, Bruglia S, Guarneri C, Vaccaro M. What syndrome is this? Kabuki make-up syndrome. Pediatric Dermatology 2007;24(3):309.
  6. Schrander-Stumpel CT, Spruyt L, Curfs LM, Defloor T, Schrander JJ. Kabuki syndrome: Clinical data in 20 patients, literature review, and further guidelines for preventive management. Am J Med Genet A 2005, Jan 30;132A(3):234-43.
  7. Genetics Home Reference — Noonan Syndrome. Available from:  http://ghr.nlm.nih.gov/condition/noonan-syndrome. Accessed 22 Sep 2012.
  8. Rare Diseases | National Board and Health and Welfare of Sweden — Noonan Syndrome. Available from:  http://www.socialstyrelsen.se/rarediseases/noonansyndrome. Accessed 22 Sep 2012.
  9. CheckOrphan — Hardikar Syndrome. Available from:  http://www.checkorphan.org/disease/hardikar-syndrome. Accessed 22 Sep 2012.

Symptom Management

Kabuki syndrome is a genetic disorder that tends to involve several organs and multiple body systems [1,2]. Some of the clinical features are more common than others. However, not all individuals experience the same set of symptoms. Moreover, most individuals with KS do not have all of the clinical features discussed here [3]. Clinical manifestations of KS include both structural anomalies as well as functional differences [4]. Evaluation of syndrome features and management guidelines has been divided into categories based on the body systems involved for further discussion. While there is currently no cure for KS, preventative management of symptoms aims to reduce the risk of complications as well as to improve the quality of life for both patients and their families.

Growth and feeding [1-5]

Patterns of growth impairment are usually not evident in newborns with Kabuki syndrome. Most individuals affected with the syndrome, however, may develop failure to thrive and growth deficiency during their first year of life. Such growth impairment often develops and becomes more pronounced over time. Feeding difficulties, gastroesophageal reflux, or malabsorption tend to exacerbate these patterns of growth deficiency. Microcephaly occurs in approximately 1/4 to 1/3 of KS patients. Growth hormone deficiency is not usually characteristic of the syndrome. Only a few cases have been identified.

Infancy and Childhood
Growth impairment Monitor height and weight
Consider referral to endocrinology if rate of growth abnormal
Gastroesophageal reflux Consider  pH probe study
Failure to thrive | Difficulties sucking and swallowing Consider barium study in those with abnormal suck or swallow
Consider gastrostomy tube placement in those with severe feeding difficulties
PEG tube (percutaneous endoscopic gastrostomy)
Microcephaly Monitor head circumference
Complete or partial growth hormone deficiency (see Endocrine) Exogenous growth hormone therapy
Adolescence and Adulthood
Obesity | Increased body mass index Monitor height, weight, and body mass index
Consider referral for nutrition consult to advise on healthy diet and exercise if patient develops obesity in later childhood or at puberty

Development and Behavior [1-10]

Most children with the syndrome present with cognitive difficulties and/or intellectual disability, usually in the mild to moderate range. Most are developmentally delayed in several areas. However, no clear pattern of specific development difficulties have been reported [4]. Standardized psychoeducational testing and consultation with a developmental pediatrician or psychiatrist may help monitor developmental milestones. Relative strengths in verbal and nonverbal reasoning have been reported in these children, with relative weakness in visuospatial skills and poor attention span. The relative strengths of receptive language in relation to expressive language skills appear to be inconclusive at this time. That said, consultation with a speech therapist may help with delayed language acquisition and impaired oral motor function.

Autism is rare but has been reported with features ranging from pervasive developmental disorder (PDD) to autistic-like to autistic disorder.

The majority of these children often have hypotonia and may lag behind in acquiring gross motor developmental milestones. That said, most individuals are able to speak and to ambulate. Hypotonia, seizures and other neurologic symptoms are further discussed below.

Infancy and Childhood
Developmental Delay Consider referral to a developmental pediatrician or psychiatrist
Monitor developmental milestone with ongoing review and assessment by the local multidisciplinary child development team
Inquire about early intervention services
Review ongoing special educational needs with psychoeducational assessment
Consider referral to speech language therapist as required
Autism (relatively rare in KS children) Consult with the local multidisciplinary child development team for ongoing treatment and assessment
Tailor early intervention treatment for the child
Consider referral to a speech language therapist for delayed language acquisition
Behavior Consider an individual assessment of behavior problems as necessary
Provide interventions tailored to the specific needs of the child
Adolescence and Adulthood
Developmental Delay Continue to monitor developmental milestones and language acquisition
Continue to monitor and consult speech language therapist in areas of language development and literacy skills
Behavior Provide families and individuals with ongoing support and behavioral management advice
Provide access to social skills training, speech therapy (as required), and programs that teach employment skills and independent living skills as necessary

Neurologic Findings

As mentioned previously, hypotonia (which may be exacerbated by joint hyperextensibility), delays in gross motor skills, and seizures have been frequently reported in most children with KS [1,2]. Symptoms of hypotonia and joint hyperextensibility tend to improve with age. Other neurologic findings may include ptosis (image), an expressionless face, and a drooping lower lip [2]. Dysarthria and dyspraxia are not uncommon [2]. Treatment available includes physical therapy and speech therapy [2,5].

Other neurological features may include poorly coordinated sucking and swallowing. This often results in feeding difficulties, as discussed earlier. Various intervention options and a more detailed discussion are available in the Growth and Feeding section above.

Seizures have been reported in approximately 10 to 39% of KS patients [4]. Seizure onset tends to vary from the neonatal period up to 12 years of age [2]. Symptoms can often be managed and assessed through pediatric neurology [2,5]. Most of these children have a favorable seizure outcome [2].

Infancy and Childhood [1,2,5]
Hypotonia Consider referral to pediatric neurology
Refer for physical therapy assessment upon diagnosis
Review physiotherapy support at regular intervals, as required
Avoid invasive diagnostic tests once KS diagnosis has been firmly established
All Ages [1,2,5]
Seizures Consider referral to pediatric neurology
Consider electroencephalograms (EEGs) and MRI scan if seizures occur
Manage seizure symptoms with standard epileptic treatment (medication)
Structural central nervous system (CNS) malformations Consider head-imaging studies, e.g. MRI scan, in cases of suspected intracranial pathology, such as microcephaly, macrocephaly, polymicrogyria, and subarachnoid cyst

Cardiovascular (Heart)

Visceral anomalies, such as cardiovascular defects, are one of the more common clinical characteristics found in KS. Congenital heart defects more commonly reported in KS may include left sided obstructive lesions, aortic lesions or dilatation, ventricular septal defect (VSD), atrial septal defect (ASD), juxtaductal coarctation of the aorta, patent ductus arteriosus, and transposition of great vessels [1,2].

Atrial septal defect and ventricular septal defect are the most commonly seen structural anomalies of the heart in KS patients [5]. Screening and further assessment are usually performed at the time of a diagnosis of KS.

In VSD, the wall that separates the right and left — the ventricular septal — may bear one or more holes [13]. If the opening in the wall becomes too large, it may result in blood being pumped into the lungs when it is not supposed to, potentially leading to heart failure [13]. VSD is one of the more common heart malformations seen in KS.

In ASD, an abnormal opening is present in the wall between the right and left atria [15]. Partitioning of the two atria is essential in order to keep oxygen-rich blood from mixing with oxygen-poor blood [16]. If the size of the opening in the atrial septum is large enough, oxygen-rich blood from the left atrium may leak into the stores of oxygen-poor blood in the right atrium [15]. Potential complications of ASD may include atrial fibrillation, heart failure, pulmonary over-circulation, pulmonary hypertension, and/or stroke.

All Ages [1,2,5]
Structural abnormalities, e.g. aortic lesions, aortic coarctation, ASD, VSD, aortic dilatation Consider referral to cardiologist upon detection of cardiac anomalies
Cardiac catheterization [18] as treatment or as diagnostic assessment
Coronary angioplasty [19] to restore blood flow to the heart
Careful assessment of contraindications prior to any surgical procedures due to the potential increased risk of aortic aneurysm
Arrhythmia (relatively rare) Monitor with electrocardiogram (ECG)
Blood pressure Take measurements annually in all patients

Respiratory

Abnormalities in the respiratory system is not commonly seen in individuals with KS. Recurrent pneumonia may occur but is believed to have an immunologic basis (see our Immunologic section below).

Endocrinologic [2,5]

Most children with KS progress through puberty normally [5].  Premature thelarche in girls is the more frequently reported endocrinologic finding in KS but most often improves with time [4].

Reports of hypoglycemia, congenital hypothyroidism, and growth hormone deficiencies have been rare.

Infancy and Childhood [1,2,5]
Hypoglycemia Monitor blood glucose levels if suggestive symptoms occur
Adolescence and Adulthood [1,2,5]
Premature thelarche in girls Monitor pubertal development with physician
Consider endocrinological consult if concerns do not resolve on their own or become problematic
Management of menstruation Use of combined oral contraceptive (COC) or Depo-Provera as means to suppress or lighten periods

Ophthalmologic (Vision)

Severe visual impairment is fairly uncommon. However, approximately one-third to one-half of KS individuals show ophthalmologic anomalies [2,3]. The most common abnormalities include ptosis, strabismus, and blue sclerae. Less common are refractive errors, delayed visual maturation with nystagmus, Peters’ anomaly, palsy of the third cranial nerve, Marcus Gunn’s phenomenon, cataracts, optic nerve hypoplasia, megalocornea, microcornea, and retinal and ocular colobomas [2].

Infancy and Childhood [1,2,5]
Ophthalmic problems Consult physician for a formal ophathalmological assessment upon KS diagnosis
Follow up with annual vision screening
Structural ocular abnormalities Consider referral to a pediatric ophthalmologist as required
Manage ophthalmologic care with standard treatment
Consider surgical correction for severe structural abnormalities
Recurrent eye infections Consult ophthalmologic or oculoplastics care team to manage recurrent or severe eye infections associated with lacrimal duct anomalies

Otolaryngologic Findings and Hearing

Recurrent otitis media occurs frequently in individuals with KS [2]. Factors that may contribute to ear infections include cleft palate complications (see Craniofacial and Dental section), as well as increased susceptibility to infections (see Immunologic / Hematologic section). Chronic otitis media can sometimes lead to conductive hearing loss, which occurs in close t0 20-30% of KS patients [2]. Sensorineural hearing loss is often associated with Mondini dysplasia of the inner ear [5].

Ear dysmorphia is often characterized by prominent, cup-shaped ears [2,5]. In addition to Mondini dysplasia, inner ear malformation may also include vestibular and aqueductal enlargement, aplastic cochlea and aplastic semicircular canals [4].

Infancy and Childhood [1,2,5]
Hearing Impairment Monitor with annual hearing evaluations
For home care, flush wax buildup out of the ear gently with ear syringes and warm water and/or wax softeners (e.g. Cerumenex)
Vestibular symptoms, inner ear abnormalities Consider vesticular assessment
Chronic otitis media Consider referral to ear, nose, throat (ENT) for recurrent ear infections
Consider grommet or T-tubes for conductive hearing loss associated with chronic otitis media
Hearing loss (conductive) Consult ENT for treatment options, such as amplification, speech and language therapy, cochlear implantations, surgical correction for ossicular malformation
Hearing loss (sensori-neural) Consider vestibular assessment as well as an MRI scan of the petrous temporal bone to rule out Mondini dysplasia

Craniofacial and Dental

The characteristic facial features — considered to be part of the diagnostic criteria — are seen in all patients with KS. These include eversion of the lateral third of the lower eyelid — reminiscent of a Kabuki actor’s makeup [1], long palpebral fissures, arched and broad eyebrows, short nasal septum, depressed nasal tip, and prominent, large ears [1,2]. See Symptoms for images of some of these characteristic features.

Cases of orofacial clefts, including cleft lip and/or palate, have been reported in approximately one third of individuals affected by the syndrome [4]. High-arched palate is seen in almost three quarters of KS patients [1,4]. Orofacial clefts and palatal abnormalities may increase the chance of feeding difficulties, recurrent ear infections, as well as speech difficulties [4].

Dental abnormalities have been observed in 68% of KS patients [1]. These may include malocculsion, hypodontia, and abnormal tooth shape [17].

All Ages [1,2,5]
Cleft palate Careful examination of palate upon KS diagnosis
Consider referral to an ENT and a cleft team for possible surgical intervention as required
Dental hygiene and management Ensure good dental hygiene practices
Consider referral to pediatric dentistry for multidisciplinary management
Dental anomalies Careful dental evaluation for hypodontia/malocclusion/other dental anomalies
Consider referral to orthodontics in cases of missing teeth or malocclusion

Gastrointestinal (GI)

Structural and functional gastrointestinal abnormalities are relatively rare in KS patients [2,17]. The most prevalent visceral abnormalities in KS are those of the anus or rectum [20]. These may include imperforate anus (or anal atresia), anovestibular fistula (AVF), or anteriorly placed anus [2].

Other possible gastrointestinal abnormalities include biliary atresia, neonatal sclerosing cholangitis, diaphragmatic hernia, secretory diarrhea, and more rarely, malrotation of the intestines [2].

Infancy and Childhood [1,2,5]
GI visceral anomalies Consider referral to pediatric gastroenterologist as required
Standard surgical correction of GI abnormalities, including open procedures, minimally invasive surgery, and endoscopic techniques

Kidneys and Genitourinary

Renal abnormalities occur in over 25% of KS patients [2]. Possible structural abnormalities of the renal system may include underdevelopment (renal hypoplasia or renal dysplasia), renal agenesis, malposition of the kidneys, hydronephrosis, or fusion defects of the kidneys [6,17].

Genitourinary anomalies, such as cryptorchidism, micropenis and hypospadias have been reported to occur in a proportion of male patients [17]. Amongst females, hypoplasia of the labia has been found to occur [17].

All newly diagnosed KS patients should undergo renal assessment, such as ultrasound examination of the kidneys [6].

Infancy and Childhood [1,2,5]
Visceral malformations Renal ultrasound and careful physical examination for cryptorchidism upon KS diagnosis
Consider referral to nephrology or urology as required

Musculoskeletal and Skin

Unusual dermatoglyphic patterns, such as persistent fingertip pads, are found in 88% of individuals with KS [2,17].

Skeletal abnormalities commonly seen in KS may include short and incurved fifth digits with short fifth metacarpals, cone-shaped epiphyses of the proximal second through fifth phalanges, rib anomalies, hip dislocation, patella dislocation, and structural anomalies of the vertebra, such as butterfly vertebrae, sagittal cleft, hemivertebrae, spina bifida occulta, narrow intervertebral disc space, and varying degrees of scoliosis [1,2].

Cranial abnormalities may include coronal synostosis, metopic synostosis, incomplete development of the frontal and/or maxillary sinuses (image), digital impression of the skull, and underdevelopment of the mastoid processes [2].

All Ages [1,2,5]
Skeletal abnormalities Radiographs of the spine upon diagnosis of KS
Monitor for the development of scoliosis
Consider referral to orthopedics for spinal abnormalities, scoliosis, or recurrent joint dislocations
Evaluation and management of musculoskeletal difficulties by multidisciplinary team via physiotherapy, occupational therapy, or orthotics team as required

Immunologic / Hematologic

Increased susceptibility to infections is relatively common in individuals with KS [2,17]. Recurrent respiratory tract infections, including pneumonia, as well as ear infections are not uncommon [1,2,4]. Recurrent otitis media may be related to cleft palate, possibly leading to conductive hearing impairment [1].

Immunodeficiencies, for example, hypogammaglobulinemia, have been seen in the syndrome [1,2]. Reduced levels of immunoglobulins IgG, IgA, and IgM in the blood have been reported in these cases [20].

Further, a proportion of KS patients may also have an increased risk for autoimmune disease, such as idiopathic thrombocytopenic purpura (ITP) autoimmune hemolytic anemia [2]. Low levels of serum IgA may occur in association of ITP [4].

All Ages
Immunity Monitor T cell levels, including T cell subsets and immunoglobulin at the time of diagnosis
Follow regular immunization schedule if blood cell and immunoglobulin levels appear normal
Consider referral to pediatric immunology
Respiratory tract infections Monitor for frequent sinopulmonary infections
Opsonization by complement proteins, e.g. C3b, may target and bind directly to the surface of foreign organisms and subsequently may act to ‘tag’ these foreign particles for destruction by phagocytic cells
Monitor immunoglobulin levels if multiple infections occur
Autoimmune disease Check complete blood count and thyroid function every two to three years
Monitor for evidence of ITP or autoimmune hemolytic anemia, e.g. vitiligo

References

  1. Matsumoto N, Niikawa N. Kabuki make-up syndrome: A review. Am J Med Genet C Semin Med Genet 2003, Feb 15;117C(1):57-65.
  2. Adam MP, Hudgins L. Kabuki syndrome: A review. Clin Genet 2005, Mar;67(3):209-19.
  3. Kawame H, Hannibal MC, Hudgins L, Pagon RA. Phenotypic spectrum and management issues in Kabuki syndrome. J Pediatr 1999; Vol. 134 (4), 480-485.
  4. GeneReviews™ [Internet]. Kabuki Syndrome — NCBI Bookshelf.  Available from:  http://www.ncbi.nlm.nih.gov/books/NBK62111. Accessed 22 Feb 2012.
  5. Guidelines | The Dyscerne Project. Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome: A Clinical Guideline. University of Manchester (2010). Available from:  http://www.dyscerne.org/dysc/digitalAssets/0/264_Kabuki_Guidelines.pdf. Accessed 27 Feb 2012.
  6. The Swedish Information Centre for Rare Diseases. Kabuki Syndrome — Rare Diseases. Available from:  http://www.socialstyrelsen.se/rarediseases/kabukisyndrome. Accessed 27 Feb 2012.
  7. White SM, Thompson EM, Kidd A, Savarirayan R, Turner A, Amor D, et al. Growth, behavior, and clinical findings in 27 patients with kabuki (niikawa-kuroki) syndrome. Am J Med Genet A 2004, Jun 1;127A(2):118-27.
  8. Autism Research Institute. Available from:  http://www.autism.com/index.asp. Accessed 22 Sep 2012.
  9. Glatt RL. Test for Success: The Psychoeducational Assessment. Available from:  http://www.pssuccess.ca/articles/Test%20for%20Success.pdf. Accessed 22 Sep 2012.
  10. Autism Society Canada (ASC). Available from:  http://www.autismsocietycanada.ca/index.php. Accessed 22 Sep 2012.
  11. National Institutes of Health (NIH), Seizures | Medline Plus; Available from:  http://www.nlm.nih.gov/medlineplus/seizures.html. Accessed 22 Sep 2012.
  12. Salpietro DC, Guarneri F, Rigoli L, Bruglia S, Guarneri C, Vaccaro M. What syndrome is this? Kabuki make-up syndrome. Pediatric Dermatology 2007;24(3):309.
  13. Boston Children’s Hospital | Ventricular Septal Defect (VSD). Available from:  http://www.childrenshospital.org/az/Site500/mainpageS500P0.html. Accessed 22 Sep 2012.
  14. Centers for Disease Control and Prevention. Congenital Heart Defects | Ventricular Septal Defect. Available from:  http://www.cdc.gov/ncbddd/heartdefects/VentricularSeptalDefect.html. Accessed 22 Sep 2012.
  15. Boston Children’s Hospital | Atrial Septal Defect (ASD). Available from:  http://www.childrenshospital.org/az/Site477/mainpageS477P0.html. Accessed 22 Sep 2012.
  16. Centers for Disease Control and Prevention. Congenital Heart Defects | Atrial Septal Defect. Available from:  http://www.cdc.gov/ncbddd/heartdefects/AtrialSeptalDefect.html. Accessed 22 Sep 2012.
  17. Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, et al. Further delineation of kabuki syndrome in 48 well-defined new individuals. Am J Med Genet A 2005, Jan 30;132A(3):265-72.
  18. National Institutes of Health | National Heart Lung and Blood Institute. What Is Cardiace Catheterization? Available from:  http://www.nhlbi.nih.gov/health/health-topics/topics/cath/. Accessed 11 Oct 2012.
  19. National Institutes of Health | National Heart Lung and Blood Institute. What Is Coronary Angioplasty? Available from:  http://www.nhlbi.nih.gov/health/health-topics/topics/angioplasty/. Accessed 11 Oct 2012.
  20. Primary Care Pediatrics | Ontario Association of Pediatricians. Hypogammaglobulinemia. Available from:  http://www.utoronto.ca/kids/Hypogam.htm. Accessed 27 Oct 2012.

Genetic Testing

Researchers have identified mutations of the MLL2 gene as the primary underlying cause of Kabuki syndrome [1]. In recent published literature, MLL2 mutations were found in 56%-76% of individuals with KS [2].

Molecular testing and sequence analysis [2] may help detect such genetic mutations. Genetic analysis may serve to support or confirm a diagnosis that was previously based in clinical findings. It is important to note that failure to detect mutations in the MLL2 gene would not preclude the diagnosis of KS [2]. Researchers continue to search for other genes that may be involved in the development of clinical features seen in individuals affected by KS.

Currently the primary test of molecular genetic testing involves sequence analysis of the MLL2 gene [2]. The majority of cases suggested a relatively high frequency of frameshift mutations and a moderately low number of nonsense mutations [4] in the MLL2 gene.

References

  1. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet, 2010 Sep; Vol. 42 (9), 790-793.
  2. GeneReviews™ [Internet]. Kabuki Syndrome — NCBI Bookshelf;  Available from:  http://www.ncbi.nlm.nih.gov/books/NBK62111. Accessed 22 Feb 2012.
  3. Lederer D, Grisart B, Digilio M, Benoit V, Crespin M, Ghariani S, & … Verellen-Dumoulin C. (2012). Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Of Hum Genet, 90(1), 119-124.
  4. Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, et al. MLL2 mutation spectrum in 45 patients with kabuki syndrome. Hum Mutat 2011, Feb;32(2):E2018-25.

Genetic Counseling

The majority of KS cases result from sporadic, de novo mutations in the MLL2 gene [1]. In other words, these gene mutations were not inherited and the individual may have no family history of KS [2]. Further, mutations in the MLL2 gene are not detected in all cases of KS. That said, in some cases of parent-to-child transmittance, the MLL2 gene mutations are inherited in an autosomal dominant manner [3]. In other words, in these familial cases, an abnormal gene from one parent is sufficient to cause the syndrome. In autosomal dominant inheritance, when only one parent carries the affected gene, each child has a 50 % chance of inheriting KS.

For individuals identified with the MLL2 mutation, genetic counselling and the determination of genetic risk before pregnancy or family planning may be advisable [4].

The risk of inheriting the MLL2 mutation in sibs is dependent on whether the parents carry the abnormal gene [4]. If the MLL2 gene mutation is found in a parent, a 50 % chance of parent-child transmittance is likely. When the gene mutation is found in neither parent, the risk to the sibs appears to be low.

References

  1. Matsumoto N, Niikawa N. Kabuki make-up syndrome: A review. Am J Med Genet C Semin Med Genet 2003, Feb 15;117C(1):57-65.
  2. Kawame H, Hannibal MC, Hudgins L, Pagon RA. Phenotypic spectrum and management issues in Kabuki syndrome. J Pediatr 1999; Vol. 134 (4), 480-485.
  3. Genetics Home Reference [Internet]. Kabuki Syndrome — NCBI Bookshelf;  Available from:  http://www.ncbi.nlm.nih.gov/books/NBK62111. Accessed 22 Feb 2012.
  4. GeneReviews™ [Internet]. Kabuki Syndrome — NCBI Bookshelf;  Available from:  http://www.ncbi.nlm.nih.gov/books/NBK62111. Accessed 22 Feb 2012.