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 [1] [2] [3] [4]:

• 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 [1] [4].
• Intellectual disability - Present in up to 92% of patients, intellectual impairment is an important manifestation of Kabuki syndrome [2] [4]. Many patients often have a delayed development of speech along with difficulties in cognition and understanding of words [2] [4].
• Growth deficiency - Despite having a normal height at birth, postnatal growth retardation is reported in a significant percentage of cases [1] [3] [4].
• 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 [1] [2] [4].
• Skin - persistent fetal finger pads and abnormal dermatoglyphic patterns are hallmarks of Kabuki syndrome [1] [2] [3] [4].

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) [1] [2] [3] [4]. Furthermore, hearing loss, predisposition to infections and autoimmune diseases, and feeding issues are also noted [1] [2] [3] [4].

• 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]

  The syndrome is characterized by the following clinical features: Short stature Developmental delay Congenital heart disease Skeletal anomalies Cleft Palate Distinct facial features Recurrent infections (60%) 3. [immunodeficiencysearch.com]

  The University of Chicago Genetic Services Introduces New Testing for Kabuki syndrome Patients with Kabuki syndrome, also called Kabuki make-up syndrome (KMS) have characteristic facial features, short stature, congenital heart defects, skeletal anomalies [dnatesting.uchicago.edu]

• Developmental Delay

  The syndrome is characterized by the following clinical features: Short stature Developmental delay Congenital heart disease Skeletal anomalies Cleft Palate Distinct facial features Recurrent infections (60%) 3. [immunodeficiencysearch.com]

  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]

• Epilepsy

  The cumulative incidence of epilepsy related to KABUK1 up until age 13 was 45%. [ncbi.nlm.nih.gov]

  Corresponding author Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, UK. [journals.cambridge.org]

  Epilepsy and perisylvian polymicrogyria in a patient with Kabuki syndrome. Rare syndromes Syndromes affecting the heart Genodermatoses Syndromes affecting hearing Syndromes with craniofacial abnormalities. [selokids.ru]

• Feeding Difficulties

  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]

  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]

  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]

  Other symptoms include short stature, intellectual and speech problems congenital heart defects, feeding difficulties and other symptoms. What are Kabuki syndrome care options? There is no cure for Kabuki syndrome. [nicklauschildrens.org]

• Developmental Disorder

  Kabuki syndrome (KS) is a rare developmental disorder characterized by multiple congenital malformations, postnatal growth retardation, intellectual disability, and recognizable facial features. [ncbi.nlm.nih.gov]

  disorder NOS, Learning disorder NOS 319 Unspecified mental retardation, Mental deficiency NOS, Mental subnormality NOS References Wessels et al., (2002) Clinical Dysmorphol 11(2):95–102. [genedx.com]

  Test Catalog Invitae Kabuki Syndrome Panel Test description The Invitae Kabuki Syndrome Panel analyzes two genes that are associated with Kabuki syndrome, a pediatric developmental disorder characterized by distinct dysmorphic facial features, developmental [invitae.com]

• 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]

  Other common symptoms of Kabuki syndrome include developmental delay, congenital heart disease, short stature, failure-to-thrive, feeding difficulties, hyperinsulinism (HI) and recurrent infections. [chop.edu]

• High Arched Palate

  Airway assessment, congenital defects of spinal column, mid-face hypoplasia, high arched palate, and cleft palate may make airway management difficult. [accessanesthesiology.mhmedical.com]

  Common dental manifestations of Kabuki syndrome are high-arched palate, micrognathia, malocclusion, microdontia, small dental arches, hypodontia, severe maxillary recession and mid-facial hypoplasia. [ncbi.nlm.nih.gov]

  The roof of the mouth may have an abnormal opening (cleft palate) or be high and arched, and dental problems are common in affected individuals. [malacards.org]

  […] syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched [uniprot.org]

• Visual Impairment

  Kabuki syndrome (KS) is a multiple congenital anomaly syndrome in which ophthalmological examination for the early detection of ocular abnormalities is desired in order to prevent visual impairment. [ncbi.nlm.nih.gov]

  Most of the other reported ocular features are serious abnormalities that cause visual impairment. [eyewiki.aao.org]

  Some of the reported ocular features such as ptosis, cataracts, refractive errors, strabismus and retinal coloboma may cause severe visual impairment. [scielo.br]

• 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]

  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]

  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]

• Sparse Eyebrows

  […] nose flattened Sparse eyebrow hair Very small jaw Widely-spaced teeth Droopy eyelids (ptosis) Blue sclera (whites of eyes) Strabismus (eyes not aligned) These facial features are very helpful in forming an initial suspicion that a patient has Kabuki [forgottendiseases.org]

  (A) High/sparse eyebrows by Patient 2. (B) High/sparse eyebrows demonstrated by Patient 3. (C) Depressed nasal tip demonstrated by Patient 5. (D) Depressed nasal tip demonstrated by Patient 8. (E) Hyperlaxity demonstrated by Patient 8. [bmcmedgenet.biomedcentral.com]

  […] and thin eyebrow Thin, sparse eyebrows 0000535 Strabismus Cross-eyed Squint Squint eyes [ more ] 0000486 Ventricular septal defect Hole in heart wall separating two lower heart chambers 0001629 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened [rarediseases.info.nih.gov]

  More specifically, KS is characterized by the following five, mainly external, structural features: i) A dysmorphic face, including eversion of the lower lateral eyelids and arched eyebrows with sparse lateral eyebrows; ii) dermatoglyphic abnormalities [spandidos-publications.com]

• 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]

  […] and/or hearing impairments, communication delays, and autistic-like behaviors. [allthingskabuki.org]

  Additionally, The Chinese patients had higher frequency of hearing impairment but lower frequency of microcephaly, micrognathia, strabismus, abnormal dentition, fifth finger clinodactyly and fingertip pads. [ojrd.biomedcentral.com]

• Brachydactyly

  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 include high-arched palate, cleft palate, scoliosis, sagittal cleft vertebrae, vertebral osteopenia, dysplasia of femoral acetabulum, and brachydactyly. Early breast development is seen in 23% of girls. [accessanesthesiology.mhmedical.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]

  Careful positioning is required to avoid joint dislocations (especially hips). Patients with Kabuki syndrome have a strong susceptibility to infections. No specific contraindications described. [accessanesthesiology.mhmedical.com]

  This strengthens muscle tone and lessens the chance of joint dislocations. Occupational therapy helps develop coordination and fine-motor skills. Speech therapy. [hcpro.com]

  dislocation - Joint hypermobility - Any of the following immunological abnormalities - Frequent infections - Low Immunoglobulins - Autoimmunity Kabuki exclusion criteria (29370) - Those with systemic infections (unlike patients with classical hyper IgE [panelapp.genomicsengland.co.uk]

  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]

• 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]

• Neurologic Manifestation

  Neurological manifestations and CNS anomalies have been described in some patients with this condition. However, craniosynostosis has been documented in only 4 patients with KS who did not undergo operations. [ncbi.nlm.nih.gov]

  Almost all patients have mild to moderate intellectual deficit and may present with neurological manifestations such as hypotonia or seizures. Global developmental delay is frequent. [orpha.net]

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 [1] [2]. 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 [2], 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) [1] [2]. The analysis of two genes - KMT2D (involved in the autosomal dominant form) and KDM6A (responsible for sporadic forms) will confirm the diagnosis [1] [2] [3] [4] [5] [6].

• Hypogammaglobulinemia

  MANAGEMENT For patients with hypogammaglobulinemia and recurrent sinopulmonary infections, a trial of prophylactic antibiotics may be considered. [immunodeficiencysearch.com]

  We report the case of an adolescent with an uncommon combination of manifestations, including hypogammaglobulinemia and severe chronic thrombopenia associated with a novel MLL2 mutation. [ncbi.nlm.nih.gov]

Treatment of Kabuki Syndrome: There is no specific treatment for Kabuki syndrome. Instead, treatment is applied to ameliorate specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists. [kennedykrieger.org]

Management and treatment Management of KS patients focuses on manifestations; for example, treatment for feeding issues in infants may include gastrostomy tube placement. [orpha.net]

Throughout the course of rhGH treatment, the subjects' body proportions remained normal. CONCLUSIONS: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions. © 2017 S. [ncbi.nlm.nih.gov]

Treatment and prognosis Variable, depending on the degree of neuromuscular dysfunction and organ dysplasia. History and etymology "Kabuki" refers to a type of Japanese drama in which the players appear in stylized makeup. [radiopaedia.org]

Treatment and prognosis Variable, depending on the degree of neuromuscular dysfunction and organ dysplasia. History and etymology "Kabuki" refers to a type of Japanese drama in which the players appear in stylized makeup. [radiopaedia.org]

Prognosis Although morbidity is significant, prognosis is quite favorable. Life expectancy is somewhat dependent on cardiac and immunologic complications. The documents contained in this web site are presented for information purposes only. [orpha.net]

For patients with lower lip pits, a thorough evaluation should be made to distinguish between VWS and KS, as there are differences in long-term prognosis. [ncbi.nlm.nih.gov]

The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. [ncbi.nlm.nih.gov]

Summary Epidemiology KS was initially described in Japan, but has now been observed in all ethnic groups. Prevalence estimation is approximately 1:32,000. Clinical description KS has a wide and variable clinical spectrum. [orpha.net]

Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med Genet 1998;75:497-504. 14. Kallen B, Robert E, Haiirs J. The descriptive epidemiology of anophthalmia and microphthalmia. [eyewiki.aao.org]

Author information 1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3 Department of Epidemiology [ncbi.nlm.nih.gov]

Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design. [ncbi.nlm.nih.gov]

Conclusion: Association of cervical arterial disease with this syndrome has never been described, and its pathophysiology is not yet established; however, it can direct future research and maybe treatment. [surgicalneurologyint.com]

Pathophysiology[edit] The KMT2D and KDM6A genes belong to a family of genes called chromatin-modifying enzymes. [en.wikipedia.org]

Kabuki syndrome (KS) is a multiple congenital anomaly syndrome in which ophthalmological examination for the early detection of ocular abnormalities is desired in order to prevent visual impairment. [ncbi.nlm.nih.gov]

The identification of preventable causes of loss of vision underlines the value of detailed ophthalmologic examination of Kabuki syndrome patients. [scielo.br]

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2. Cheon C-K, Ko JM. Kabuki syndrome: clinical and molecular characteristics. Korean J Pediatr. 2015;58(9):317-324.
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4. Kasdon BD, Fox JE. Kabuki syndrome: diagnostic and treatment considerations. Ment Health Fam Med. 2012;9(3):171-179.
5. Makrythanasis P, van Bon BW, Steehouwer M, et al. MLL2 mutation detected in 86 patients with Kabuki syndrome; a genotype-phenotype study. Clin Genet. 2013;84:539–545.
6. 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.