Kabuki syndrome is a congenital mental retardation 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 (reminiscent of the make-up of actors ... Kabuki syndrome is a congenital mental retardation 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 (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981). - Genetic Heterogeneity Kabuki syndrome-2 (300867) is caused by mutation in the KDM6A gene (300128) on chromosome Xp11.3.
Niikawa et al. (1988) collected data from 62 patients with Kabuki syndrome from 33 institutions, almost all of them in Japan. Most of the patients had 5 cardinal manifestations: (1) a peculiar face in all cases, characterized by ... Niikawa et al. (1988) collected data from 62 patients with Kabuki syndrome from 33 institutions, almost all of them in Japan. Most of the patients had 5 cardinal manifestations: (1) a peculiar face in all cases, characterized by eversion of the lower lateral eyelid, arched eyebrows with sparse or dispersed lateral one-third, depressed nasal tip, and prominent ears; (2) skeletal anomalies in 92%, including brachydactyly V and spinal deformity with or without sagittal cleft vertebrae; (3) dermatoglyphic abnormalities in 93%, including increased digital ulnar loop and hypothenar loop patterns, absence of the digital triradius c and/or d, and presence of fingertip pads; (4) mild to moderate mental retardation in 92%; and (5) postnatal growth deficiency in 83%. Fetal finger pads, which are typical of Kabuki syndrome, occur also in the FG syndrome (305450). Early breast development occurred in 23% of infant girls. Congenital heart defects, including single ventricle with a common atrium, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of aorta, patent ductus arteriosus (see 607411), aneurysm of aorta, transposition of great vessels, and right bundle branch block, were observed in 31% of the patients. Of the 62 Kabuki syndrome patients, 58 were Japanese. The incidence of the disorder in Japanese newborns was estimated at 1 in 32,000. All cases were sporadic. The sex ratio was even, and there was no correlation with birth order. Consanguinity was not increased among the parents, and no exogenous agent could be incriminated. Three of the 62 patients had a Y chromosome abnormality involving Yp11.2. In general, the findings of Niikawa et al. (1988) were considered compatible with an autosomal dominant disorder in which each patient represents a fresh mutation. A mutation rate was calculated at 15.6 x 10(-6) per gamete per generation. (The abstract of Niikawa et al. (1988) incorrectly stated the rate to be 15.6 x 10(6).) The possibility of the location of the gene in the pseudoautosomal region of the X chromosome was also raised. Clarke and Hall (1990) described 3 unrelated Caucasian children with this syndrome. Gillis et al. (1990) described the disorder in a child of Arab descent. Philip et al. (1992) studied 16 non-Japanese cases from Europe and North America. They concluded that the facial phenotype is specific and easily recognizable regardless of ethnic origin. Postnatal growth retardation and mild mental retardation were confirmed to be cardinal manifestations. Significant neurologic dysfunction other than mental retardation and joint hypermobility appeared to be more common in the non-Japanese patients. Hughes and Davies (1994) presented 20 unselected cases with a definitive diagnosis of Kabuki syndrome: 6 boys and 14 girls, ranging in age from 10 months to 13 years. The incidence of heart abnormalities in these children was almost twice that previously reported (55%) and juxtaductal coarctation occurred with a frequency of 25%. One of the patients pictured by Hughes and Davies (1994) showed the accentuated depression that is often seen below the midpoint of the lower lip. Ilyina et al. (1995) reported 10 patients of European ancestry from Byelorussia, Russia, and Moldavia. They emphasized prominent and broad philtrum as an important component. Some clinical manifestations were observed in parents and other relatives in 3 generations of 3 families. Ilyina et al. (1995) favored autosomal dominant inheritance with variable expressivity. Burke and Jones (1995) reported 8 cases of Kabuki syndrome in non-Japanese patients. They commented that the phenotype appears to evolve over time, making the diagnosis difficult in infancy. They stated that cleft palate occurs in about 40% of patients. Galan-Gomez et al. (1995) described Kabuki syndrome in 5 Spanish children, 3 females and 2 males. Sagittal vertebral clefts and dermatoglyphic abnormalities were present in all 5; general heart defects were present in 4. Halal et al. (1989) reported an instance of probable autosomal dominant inheritance of the Kabuki syndrome; a father and his 2 children were affected. The father had milder symptoms than the offspring, but had typical facial changes and was of normal intelligence. Kobayashi and Sakuragawa (1996) described a family in which a 45-year-old business man and his 17-year-old daughter, born to nonconsanguineous parents, were affected. The father had characteristic facial abnormalities of Kabuki syndrome, including long palpebral fissures, long eyelashes, and a prominent nose. He was of normal stature and there were no deformities of the fingers, feet, or ribs. However, he had all ulnar loop patterns on the fingertips, and lacked palmar triradii c and d. His mental status was above average. In the daughter, a ventricular septal defect had been surgically closed at age 6 years. Her psychomotor development was delayed and school performance was poor. She was 146.5 cm tall at the age of 17. She had epicanthic folds, long palpebral fissures, high-arched eyebrows sparse in the lateral one-third, a broad and depressed nasal tip, a short nasal septum, and large malformed ears. Her fingers were stubby with bilateral clinodactyly of the fifth fingers, and the first toes were hyperplastic. On fingertips she had an increased number of ulnar loops, and she lacked palmar triradii c and d. There was a hypothenar ulnar loop, and fingertip pads were found on all fingers, a common finding in Kabuki syndrome. Her IQ was estimated to be 60. The mother was of normal height and had no minor anomalies or abnormal dermatoglyphic patterns. Silengo et al. (1996) reported an Italian girl with typical findings of Kabuki syndrome and a mildly affected mother. The fact that males and females are equally affected, that the consanguinity rate is not increased, that parents and other relatives of patients show a facial resemblance, and that the condition is transmitted vertically with variable clinical manifestations in familial cases are all compatible with autosomal dominant inheritance. Sporadic cases may represent new mutations. Tsukahara et al. (1997) described 4 individuals with Kabuki syndrome in 2 families. In family 1, the proposita, a 2-year-old girl, and her mother had typical Kabuki syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl, and her mother had typical Kabuki syndrome. The proposita died at age 6 months as a result of complications of a cardiac malformation. In a girl with Kabuki syndrome, Lerone et al. (1997) described conical incisors, hypodontia, hypoplastic nails, and brittle hair. Although abnormal teeth have commonly been described in this disorder, hair abnormalities have never been investigated. Dominant inheritance with variable expressivity was supported by the mother and child reported by Courtens et al. (2000). The 18-month-old daughter had facial features characteristic of Kabuki syndrome, prominent fingertips, a midsagittal cleft of vertebral body thoracic-4, hypotonia, and psychomotor retardation. The mother had a similar facial appearance, prominent, cup-shaped ears, abnormal dentition, early breast development, and low normal intelligence. The maternal grandmother had the same facial appearance and 3 maternal aunts reportedly likewise showed these features. Microscopic examination of the hair of the proposita showed abnormalities consisting of trichorrhexis nodosa, twisting of the hair shafts, and irregularity of the diameter of the hair, all changes similar to those reported by Lerone et al. (1997). Shotelersuk et al. (2002) described 6 Thai children with the Kabuki syndrome, including monozygotic twins who are discordant for the syndrome. In another family, a mother had a facial appearance similar to that of her affected son, suggesting autosomal dominant inheritance. Common findings included lower lip pits with or without symmetrical lower lip nodules and pilonidal sinuses. Early eruption of the 2 lower central incisors, transient hyperthyrotropinemia in infancy, and aplasia cutis were also observed. Wilson (1998) compared 8 new and 5 previously illustrated cases of this syndrome with those in the literature, providing data on 183 cases. A total of 108 non-Asian patients had been reported. Although hydronephrosis had been reported in a few cases of Kabuki syndrome, Ewart-Toland et al. (1998) reported the first cases of Kabuki syndrome with hepatic anomalies. They described 2 patients with renal and/or hepatic anomalies requiring transplantation. Both patients had the characteristic facial appearance of children with Kabuki syndrome, postnatal growth deficiency, and developmental delay. At birth, 1 patient presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology was interpreted as neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of Kabuki syndrome, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo. Kawame et al. (1999) analyzed the clinical findings of Kabuki syndrome in 18 North American children. Most had postnatal growth retardation, and all had developmental delay and hypotonia. Feeding difficulties, with or without cleft palate, were common; 5 patients required gastrostomy tube placement. In all but 2 patients, developmental quotients/IQs were 60 or less. Seizures were seen in less than half of the patients, but ophthalmologic and otologic problems were common, particularly recurrent otitis media. Congenital heart defects were present in 7 (39%); 3 patients underwent repair of coarctation of the aorta. Other features included urinary tract anomalies, malabsorption, joint hypermobility and dislocation, congenital hypothyroidism, idiopathic thrombocytopenic purpura, and, in 1 patient, autoimmune hemolytic anemia and hypogammaglobulinemia. All patients had negative family histories for Kabuki syndrome. McGaughran et al. (2000) described 2 females with typical Kabuki syndrome who presented in the first year of life with extrahepatic biliary atresia, a previously undescribed complication of the syndrome. Selicorni et al. (2001) described a similar case of atresia of the extrahepatic bile ducts and common bile duct identified in a 44-day-old infant. A Kasai procedure was performed at that time with complete disappearance of jaundice by the age of 5 months. However, recurrence of symptoms required liver transplantation which was successfully performed at the age of 20 years; she was in good condition 5 years thereafter. Donadio et al. (2000) reported an Italian girl with Kabuki syndrome and diaphragmatic hernia. Donadio et al. (2000) reviewed 3 other cases of Kabuki syndrome with diaphragmatic defects, all of non-Asian origin. Van Haelst et al. (2000) reported 2 patients with Kabuki syndrome and stenosis of the central airways (one with local stenosis of the right upper lobe bronchus, and the other with severe bronchomalacia and an abnormal right bronchial tree), a complication not previously reported in patients with Kabuki syndrome. One of the patients also had extrahepatic biliary atresia, and the other had congenital diaphragmatic hernia. Kokitsu-Nakata et al. (1999) reported the case of a Brazilian girl with Kabuki syndrome associated with lower lip pits and anorectal anomalies. They found reports of at least 4 patients with Kabuki syndrome and anorectal anomalies (Matsumura et al., 1992). They found reports of lower lip pits only in a Kabuki syndrome patient reported by Franceschini et al., 1993. However, Makita et al. (1999) reported a 5-year-old Japanese girl with clinical manifestations of both Kabuki syndrome and the van der Woude lip-pit syndrome (VWS; 119300). Assuming that the association of the 2 syndromes was caused by a microdeletion involving putative genes for the 2 disorders, Makita et al. (1999) carried out fluorescence in situ hybridization and microsatellite analyses using PAC clones and dinucleotide repeat markers spanning the VWS1 critical region at 1q32-q41. No deletion was detected. Igawa et al. (2000) studied 3 patients with Kabuki syndrome for middle and inner ear abnormalities by using CT of the petrous bones. No middle ear abnormalities were identified, but all 3 patients had bilateral dysplasia of the inner ear (hypodysplasia of the cochlea, vestibule, and semicircular canals). Audiometry on 2 of the patients showed a sharp decrease in hearing of the high tone range, bilateral in one and unilateral in the other. The authors concluded that CT of the petrous bones and audiometry should be performed in early infancy on all patients with Kabuki syndrome. Matsune et al. (2001) described oral manifestations in 6 patients with Kabuki syndrome. These included a high-arched palate, malocclusion, microdontia, a small dental arch, hypodontia, severe maxillary recession, and midfacial hypoplasia. McGaughran et al. (2001) described 9 patients with Kabuki syndrome from New Zealand, all having the characteristic facial dysmorphism and many of the well-described associated anomalies. Some had unusual abnormalities, including diaphragmatic eventration, severe congenital mitral stenosis, idiopathic thrombocytopenic purpura, and vitiligo. They also reported Arnold Chiari type 1 malformation and epibulbar dermoids, neither of which had been previously reported in this syndrome. Digilio et al. (2001) presented the results of cardiac evaluations of 60 patients diagnosed with Kabuki syndrome at their institution. Cardiac evaluation included chest radiograph, electrocardiogram, and 2-dimensional and color Doppler echocardiography. Thirty-five of the patients (58%) had congenital heart defects. The most commonly observed defects were coarctation of the aorta (23%), atrial septal defect (20%), and ventricular septal defect (17%). Kurosawa et al. (2002) reported 4 patients with Kabuki syndrome and patellar dislocation and reviewed 6 previously reported patients with this combination. In their 4 patients, the age at diagnosis of the patellar dislocation ranged from 11 to 23 years. Of the patients in whom gender was known, 7 were female and 2 were male. The authors concluded that patellar dislocation may be frequent among older children and young adults with Kabuki syndrome, especially among obese female patients with lax knee joints. Fryns and Devriendt (1998) described an 8-year-old girl with signs and symptoms thought to be consistent with Kabuki syndrome. She also had bilateral defective, bipartite clavicles. Hinrichs et al. (2002) described 2 unrelated patients with this type of clavicular defect in association with Kabuki syndrome. Mihci et al. (2002) described a 7-year-old boy with Kabuki syndrome whose head MRI showed migration defects, including periventricular nodular heterotopia present along the walls of both lateral ventricles and an underdeveloped corpus callosum. Ming et al. (2003) reported 3 children with Kabuki syndrome who also had retinal coloboma. A diagnosis of CHARGE association (214800) was initially suggested in 2 of the patients before the typical facial features of Kabuki syndrome emerged. A review of reported cases showed that the incidence of coloboma is greatly increased in Kabuki syndrome. White et al. (2004) documented the phenotype of 27 children and adults with Kabuki syndrome from Australia and New Zealand. Parents reported a behavior phenotype characterized by the avoidance of eye contact, a love of music, and an excellent long-term memory. There was no correlation between head circumference and severity of intellectual disability. Six of their patients showed a characteristic growth profile, with failure to thrive in infancy progressing to obesity or overweight in middle childhood or adolescence. Wessels et al. (2002) reviewed the characteristics of Kabuki syndrome in 300 patients. Typical findings included mild to moderate mental retardation, fetal pads, cleft palate, and characteristic facies with long palpebral fissures, everted lower lateral eyelids, and arched eyebrows. Postnatal growth retardation and skeletal and visceral anomalies were present in a large percentage of the patients. Genevieve et al. (2004) described 8 patients from a series of 20 who had atypical findings in Kabuki syndrome. Rare or atypical features included the following: chronic and/or severe diarrhea (4/20) including celiac disease, diaphragmatic defects (3/20), pseudarthrosis of the clavicles (2/20), vitiligo (2/20), and persistent hypoglycemia (2/20). Other occasional findings were severe autoimmune thrombopenia, cerebellar vermis atrophy, and myopathic features. One patient presented with a clinical overlap with CHARGE syndrome (214800). Adam and Hudgins (2004) provided a detailed review of the clinical features, diagnostic criteria, and cytogenic abnormalities reported in Kabuki syndrome. Turner et al. (2005) reported 7 patients with Kabuki syndrome. Three patients had previously undetected ocular abnormalities, including myopia, ptosis, strabismus, and tilted discs. Four patients had nocturnal lagophthalmos (sleeping with the eyes open). There was no evidence of an 8p duplication in any of the patients. Hoffman et al. (2005) performed immunologic evaluation of 19 consecutive individuals with Kabuki syndrome and found decreased IgA levels in 15 of 19 patients (79%), 2 of whom had undetectable levels. Eight patients (42%) also had low total IgG levels, and specific IgG subclass abnormalities were found in 6 of 13 patients evaluated; IgM levels were less frequently decreased. One patient failed to generate anti-tetanus antibodies despite immunization. Hoffman et al. (2005) suggested that hypogammaglobulinemia is a frequent finding in Kabuki syndrome and noted that the pattern of antibody abnormalities resembles common variable immune deficiency (CVID; 240500).
Ng et al. (2010) performed the exome sequencing of 10 unrelated patients with Kabuki syndrome, 7 of European ancestry, 2 of Hispanic ancestry and 1 of mixed European and Haitian ancestry, and identified nonsense or frameshift mutations in ... Ng et al. (2010) performed the exome sequencing of 10 unrelated patients with Kabuki syndrome, 7 of European ancestry, 2 of Hispanic ancestry and 1 of mixed European and Haitian ancestry, and identified nonsense or frameshift mutations in the MLL2 gene in 7 patients. Follow-up Sanger sequencing detected MLL2 mutations in 2 of the 3 remaining individuals with Kabuki syndrome and in 26 of 43 additional cases. In all, they identified 33 distinct MLL2 mutations in 35 of 53 families (66%) with Kabuki syndrome (see, e.g., 602113.0001-602113.0004). In each of 12 cases for which DNA from both parents was available, the MLL2 variant was found to have occurred de novo. MLL2 mutations were also identified in each of 2 families in which Kabuki syndrome was transmitted from parent to child. None of the additional MLL2 mutations was found in 190 control chromosomes from individuals of matched geographic ancestry. Ng et al. (2010) suggested that mutations in MLL2 are a major cause of Kabuki syndrome. Hannibal et al. (2011) identified 70 mutations in the MLL2 gene in 81 (74%) of 110 kindreds with Kabuki syndrome. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, whereas a transmitted mutation was found in 2 of 3 familial cases. Most of the variants were nonsense or frameshift mutations predicted to result in haploinsufficiency. Mutations occurred throughout the gene, but were particularly common in exons 39 and 48. The clinical features of those with or without mutations were similar, except for renal anomalies, which occurred in 47% of mutation carriers compared to 14% of those who did not have a mutation. Li et al. (2011) sequenced all 54 coding exons of the MLL2 gene in 34 patients with Kabuki syndrome and identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located throughout the gene and included 3 nonsense mutations, 2 splice site mutations, 6 small deletions or insertions, and 7 missense mutations. Li et al. (2011) compared frequencies of clinical symptoms in MLL2 mutation carriers versus noncarriers. MLL2 mutation carriers more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 showed a more typical facial gestalt (17 of 19) compared with noncarriers (9 of 15), although this result was not statistically significant (p = 0.1). Miyake et al. (2013) identified MLL2 mutations in 50 (61.7%) of 81 patients with Kabuki syndrome. Most (70%) of the MLL2 mutations were predicted to be protein-truncating. The truncating mutations were distributed throughout the coding region, whereas the nontruncating mutations were most often within or adjacent to functional domains. - Genotype-Phenotype Correlations Banka et al. (2012) analyzed the MLL2 gene in a cohort of 116 patients with Kabuki syndrome, including 18 patients previously reported by Hannibal et al. (2011), and identified MLL2 variants in 74 (63.8%). Systematic Kabuki syndrome facial morphology study suggested that nearly all patients with typical Kabuki syndrome facial features have pathogenic MLL2 mutations, although the disorder can be phenotypically variable. In addition, Banka et al. (2012) showed that KABUK1 patients were more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations, and palatal malformations in comparison with MLL2 mutation-negative patients. Banka et al. (2012) concluded that the genetic heterogeneity of Kabuki syndrome is not as extensive as previously suggested; however, given the phenotypic variability of the disorder, MLL2 testing should be considered even in atypical patients. Miyake et al. (2013) screened 81 patients with Kabuki syndrome for mutations in the MLL2 and KDM6A genes and identified MLL2 mutations in 50 (61.7%) and KDM6A mutations in 5 (6.2%). Patients with MLL2 truncating mutations (70%) had facies that were more typical of those seen in the patients originally reported with Kabuki syndrome. High-arched eyebrows, short fifth fingers, and infantile hypotonia were more commonly seen in patients with MLL2 mutations than in those with KDM6A mutations. Only half of the patients with MLL2 mutations had short stature and postnatal growth retardation, compared to all of the patients with KDM6A mutations. - Exclusion Studies Bottani et al. (2006) screened the TGFBR1 (190181) and TGFBR1 (190182) genes in 14 typical Kabuki patients and found no mutations. In a girl with Kabuki syndrome, Maas et al. (2007) identified a heterozygous de novo 250-kb deletion in the MACROD2 gene (611567) at chromosome 20p12.1. No deletions or pathogenic mutations in the MACROD2 or FLRT3 (604808) genes were identified in 19 additional patients with Kabuki syndrome. Among 43 Japanese patients with Kabuki syndrome, Kuniba et al. (2008) did not find mutations or deletions in the MACROD2 or FLRT3 genes. Of 34 patients with Kabuki syndrome, Li et al. (2011) failed to find mutations in the MLL2 gene in 15. Mutation-negative patients were subsequently tested for mutations in 10 functional candidate genes, but no convincing causative mutations could be identified. Li et al. (2011) concluded that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations but that there is further genetic heterogeneity accounting for MLL2 mutation-negative patients.
Consensus clinical diagnostic criteria for Kabuki syndrome (KS) have not been established. Individuals with this condition have characteristic facial features, in addition to a variety of congenital anomalies, which suggest the diagnosis. Listed below are the five cardinal manifestations as defined by Niikawa et al [1988]....
DiagnosisClinical Diagnosis Consensus clinical diagnostic criteria for Kabuki syndrome (KS) have not been established. Individuals with this condition have characteristic facial features, in addition to a variety of congenital anomalies, which suggest the diagnosis. Listed below are the five cardinal manifestations as defined by Niikawa et al [1988].Typical facial features [Niikawa et al 1988, Wilson 1998, Armstrong et al 2005, Schrander-Stumpel et al 2005, Hannibal et al 2011]:Elongated palpebral fissures with eversion of the lateral third of the lower eyelidArched and broad eyebrows with the lateral third displaying sparseness or notchingShort columella with depressed nasal tipLarge, prominent, or cupped earsSkeletal anomalies:Spinal column abnormalities, including sagittal cleft vertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosisBrachydactyly VBrachymesophalangyClinodactyly of fifth digitsDermatoglyphic abnormalities: persistence of fetal fingertip pads Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers.Mild to moderate intellectual disabilityPostnatal growth deficiencyStructural anomalies in KS can include the following [Matsumoto & Niikawa 2003, Armstrong et al 2005, Schrander-Stumpel et al 2005]:Congenital heart defectsGenitourinary anomalies, including cryptorchidism in malesCleft lip and/or palateGastrointestinal anomalies, including anal atresiaOphthalmologic anomalies, including ptosis and strabismusDental anomalies, including widely spaced teeth and hypodontiaEar pits (a potentially helpful diagnostic clue when seen with other typical findings) Functional differences can include the following:Increased susceptibility to infections and autoimmune disordersSeizuresEndocrinologic abnormalities, including isolated premature thelarche in femalesFeeding problemsHearing lossMolecular Genetic Testing Gene. KMT2D (formerly MLL2) and KDM6A are the only genes in which mutations are known to cause KS.Evidence for possible locus heterogeneity. No other loci are known to be involved in causing KS. However, for approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore locus heterogeneity for one or more as-yet unidentified genes remains a possibility [Bögershausen & Wollnik 2013].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Kabuki Syndrome (KS)View in own windowGene SymbolTest MethodMutations DetectedTest AvailabilityKMT2D (formerly MLL2)Sequence analysisSequence variants 1, 2ClinicalDeletion/duplication analysis 3Exonic or whole-gene deletions 4KDM6ASequence analysisSequence variants 2ClinicalDeletion/duplication analysis 3Exonic or whole-gene deletions 51. KMT2D coding region sequencing detects mutations in about 52%-76% of individuals with a clinical diagnosis of KS [Hannibal et al 2011, Li et al 2011, Micale et al 2011, Paulussen et al 2011, Banka et al 2012, Makrythanasis et al 2013]. Mutations in KDM6A were found in 3/32 individuals with a clinical diagnosis of Kabuki syndrome in whom a KMT2D mutation was not identified [Miyake et al 2013].2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. Banka et al [2013]5. Detection frequencies unknown; 3/22 individuals with a clinical diagnosis of Kabuki syndrome in whom a KMT2D mutation was not identified had partial- or whole-gene deletions of KDM6A [Lederer et al 2012].Interpretation of test resultsGiven the current mutation detection rate, failure to identify a mutation would not preclude the diagnosis of KS. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandThe diagnosis is primarily established by clinical findings. A phenotypic scoring system has been developed, which may help to distinguish between those who have a KMT2D mutation and those who do not (see Table 2; see also Genotype-Phenotype Correlations). The higher the score, the more likely that an individual has a KMT2D mutation. Molecular testing (sequence analysis and deletion/duplication analysis) of KMT2D confirms the diagnosis in a majority of cases. If no mutation is identified in KMT2D, sequence analysis and deletion/duplication analysis of KDM6A should be pursued.Array comparative genomic hybridization (aCGH) can be considered to exclude cytogenetic abnormalities that produce phenotypic overlap with KS. Table 2. Proposed Phenotypic Scoring System for Kabuki SyndromeView in own windowClinical FindingPossible ScorePhenotypic Feature DetailsFacial features1-5 points 1Arched eyebrows, sparse lateral on third Blue sclerae Everted lower eyelids Long palpebral fissures Ptosis Strabismus Large dysplastic ears Broad nasal root Flat nasal tip Abnormal dentition Oligodontia High or cleft palate Micrognathia Thin upper and full lower lip Lip nodulesLimb/extremity features0-1 point 2Brachy- or clinodactyly Hip dislocation Lax joints Persistent fetal padsMicrocephaly1 pointShort stature1 pointHeart1 pointKidney1 pointTOTAL0-10 points 3Adapted from Makrythanasis et al [2013]1. 0-3 features = 1 point; 4-6 features = 2 points; 7-9 features = 3 points; 10-12 features = 4 points; 13-15 features = 5 points2. 0-1 feature = 0 points; 2-4 features = 1 point3. Those with a KMT2D mutation had a mean score of 6.1, while those without a KMT2D mutation had a mean score of 4.5Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family. Note: (1) No unaffected female heterozygotes (“carriers”) for X-linked KS have been reported to date (see Genetic Counseling) and (2) Identification of female carriers for X-linked KS requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected relative is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in KMT2D or KDM6A.
This section summarizes findings in more than 350 individuals with Kabuki syndrome (KS) [Niikawa et al 1988, Wilson 1998, Kawame et al 1999, Matsumoto & Niikawa 2003, Armstrong et al 2005, Schrander-Stumpel et al 2005]....
Natural History This section summarizes findings in more than 350 individuals with Kabuki syndrome (KS) [Niikawa et al 1988, Wilson 1998, Kawame et al 1999, Matsumoto & Niikawa 2003, Armstrong et al 2005, Schrander-Stumpel et al 2005].Growth and feeding. Neonates with KS exhibit normal growth parameters. However, postnatal growth retardation is relatively common (35%-81%). Microcephaly may or may not accompany short stature. Growth hormone deficiency has been reported (see Endocrine) but is not common. Feeding difficulties are quite common (~70%); however, severity is variable [Kawame et al 1999]. 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. Development and behavior. In their series of 62 affected individuals, Niikawa et al [1988] reported that intellectual disability, usually in the mild to moderate range, was a cardinal 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 [Matsumoto & Niikawa 2003]. A more recent review in which authors excluded reports judged to be less thorough or less diagnostically clear calculated an overall frequency of intellectual disability closer to the original estimate [Schrander-Stumpel et al 2005]. Most individuals with KS are able to speak and to ambulate. Rare individuals are non-ambulatory but able to speak; others are nonverbal with no significant motor impairment [Kawame et al 1999]. Vaux et al [2005] report an average age to walk unassisted of 20 months with a range of 15 to 30 months in 15 individuals with Kabuki syndrome. In this series, single words were spoken by 21 months on average, with a range of 10 to 30 months. Thus far, no factors allow for early prognostication.No clear pattern of specific developmental difficulties has emerged. Limited evidence suggests that tasks such as grammatic construction are of particular difficulty for individuals with KS [Defloor et al 2005]. Mervis et al [2005] performed standardized neuropsychological testing on 11 children and adolescents with Kabuki syndrome and reported relative strengths in verbal and nonverbal reasoning, with relative weakness in visuospatial skills. Receptive language skills were also greatly superior to expressive skills in this study; in contrast, other authors have reported superior expressive language [Vaux et al 2005]. Individuals with KS tend to be described as pleasant and outgoing. In their series of 11 children and adolescents, Mervis et al [2005] report that, overall, the participants’ behavioral difficulties did not surpass those expected for their chronologic age. Autism is a rare but described finding. Ho & Eaves [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 at a level above that seen in the general population. As KS becomes more widely recognized, the true incidence of social and communicative difficulties will become apparent.Neurologic. 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 brain imaging at some point 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 [Ciprero et al 2005]. 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 [Kawame et al 1999, Armstrong et al 2005]. Endocrine. Premature thelarche in girls is the most common endocrine abnormality described (7%-50%). This finding does not represent premature puberty and is likely to resolve with time. Hypoglycemia, congenital hypothyroidism, and growth hormone deficiency are rarely reported findings. Ophthalmologic. Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, and corneal abnormalities such as Peters anomaly. Optic nerve hypoplasia, cataracts, Duane anomaly, pigmentary retinopathy, and Marcus Gunn phenomenon (also referred to as jaw winking) can also be seen [Ming et al 2003]. Severe visual impairment, however, is rare [Kawame et al 1999]. As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. On the other hand, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring [Toriello & Droste 2003].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 [Matsumoto & Niikawa 2003]. 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, and aqueductal enlargement have been reported [Tekin et al 2006].Craniofacial. Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [Iida et al 2006]. Almost three quarters of affected individuals have a high-arched palate. As with all children with palatal abnormalities, 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 [Matsumoto & Niikawa 2003]. 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) are considered part of the diagnostic criteria of KS, and are 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 [Matsune et al 2001]. Abnormally shaped teeth, small teeth, widely-spaced teeth, and malocclusion have also been described.Gastrointestinal. Abnormalities involving the gastrointestinal system are not common in KS; however, anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus have been reported in a number of individuals, primarily in females [Matsumura et al 1992]. Congenital diaphragmatic hernia and eventration of the diaphragm have also been described [Niikawa et al 1981, Kawame et al 1999]. The risk of neonatal cholestasis from a variety of causes is increased [Isidor et al 2007].Genitourinary. Renal and urinary tract anomalies are seen in more than 25% of affected individuals [Matsumoto & Niikawa 2003]. 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 [Kawame et al 1999]. Hypospadias, cryptorchidism, and (more rarely) micropenis can occur in males; females can demonstrate hypoplastic labia [Armstrong et al 2005].Musculoskeletal. Joint hypermobility is seen in 50%-75% of individuals with KS [Kawame et al 1999, Matsumoto & Niikawa 2003]. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As in 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) [Niikawa et al 1988]. 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 adolescents. Hoffman et al [2005] found 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 [Kawame et al 1999, Ming et al 2005].
Comparisons of the clinical features of individuals with clinical diagnoses of Kabuki syndrome in whom a KMT2D mutation has been identified versus those in whom a KMT2D mutation has not been identified have found several differences. ...
Genotype-Phenotype CorrelationsComparisons of the clinical features of individuals with clinical diagnoses of Kabuki syndrome in whom a KMT2D mutation has been identified versus those in whom a KMT2D mutation has not been identified have found several differences. The following ten physical features are present more commonly in those with a KMT2D mutation [Makrythanasis et al 2013]:Arched eyebrowsBlue scleraeBroad nasal rootDepressed nasal tipLarge dysplastic earsThin vermilion of the upper lip and thick vermilion of the lower lipShort statureJoint laxityIntellectual disabilityFrequent infectionsThose with a KMT2D mutation are more likely to have the distinctive Kabuki facial phenotype, which may reflect the fact that a portion of those without a KMT2D mutation may indeed have been misdiagnosed.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 [Hannibal et al 2011, Li et al 2011, Paulussen et al 2011, Banka et al 2012]. To date, only six individuals with mutations or deletions in KDM6A have been described, precluding any meaningful genotype-phenotype correlations for those who have KS as a result of mutations in this gene.
Disorders that have overlapping features with Kabuki syndrome (KS) include the following:...
Differential DiagnosisDisorders that have overlapping features with Kabuki syndrome (KS) include the following:CHARGE syndrome, particularly cleft palate, heart defects, coloboma, and growth retardation. 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), particularly cleft lip and palate, cleft palate, and lip pits. Individuals with IRF6-related disorders do not have atypical growth and development, cardiac malformations, or the typical Kabuki syndrome facies. Pterygia are not expected in people with KS.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 anomalies are renal hypoplasia and/or agenesis, while in KS renal anomalies commonly include hydronephrosis and malposition. Branchial cleft cysts may be present in BOR but have not been reported in KS. Ehlers-Danlos syndrome, hypermobility type or Larsen syndrome (see FLNB-Related Disorders), particularly significant joint hypermobility (including congenital hip dislocation and patellar dislocations) and blue sclerae. These conditions are not associated with major malformations involving other organ systems or the typical minor anomalies seen in KS.X-chromosome anomalies and a variety of other chromosome anomalies, which can present with similar facial features, congenital heart defects, and growth retardation. These can easily be distinguished from KS by a chromosome analysis or chromosomal microarray (CMA).Hardikar syndrome (OMIM 612726), 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and the needs of an individual diagnosed with Kabuki syndrome (KS), the following evaluations are recommended: ...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and the needs of an individual diagnosed with Kabuki syndrome (KS), the following evaluations are recommended: Height, weight, and head circumference are measured and plotted on standard growth charts. Evaluation for a hormone deficiency, including hypothyroidism or growth hormone deficiency, is recommended in children with abnormal growth velocity.If feeding problems are severe and/or failure to thrive is apparent, an esophageal pH probe study can be considered. A barium swallow study may assist in determining whether the suck and swallow mechanism is normal. Evaluation for developmental milestones is recommended and referral for formal developmental evaluation is indicated if delays are identified.A physical therapy evaluation is indicated in those children with KS who exhibit hypotonia.Evaluation by a neurologist is recommended in those individuals with suspected seizure activity.Brain imaging at the time of diagnosis (if not already performed) is recommended in those with headaches, ocular disturbances, otoneurologic disturbances, lower cranial nerve signs, cerebellar ataxia, spasticity, or seizures to evaluate for a Chiari 1 malformation or for a brain malformation.As the incidence of cardiac malformations is high, echocardiogram with good visualization of the aortic arch is indicated in all individuals at the time of diagnosis. Referral to a pediatric cardiologist for management should be considered if a cardiac defect is present.Because of the frequency of ocular findings, formal ophthalmologic examination at the time of diagnosis is recommended for all individuals with KS.A directed evaluation of the palate at the time of diagnosis is indicated. Individuals with cleft lip, cleft palate, submucous cleft palate, or any evidence of velopharyngeal insufficiency should be referred for otorhinolaryngology evaluation.A directed physical examination to evaluate for evidence of gastrointestinal abnormalities is indicated in neonates with KS. Evidence of cholestasis should prompt a full workup, as it would in any other child. By recognizing that eventration of the diaphragm is seen in this condition, the medical care provider can avoid further evaluation for possible phrenic nerve paralysis.Because of the frequency of renal/urinary tract anomalies, renal ultrasound examination is indicated in all individuals with KS at the time of diagnosis. Referral to a nephrologist and/or urologist is recommended for those individuals with hydronephrosis. Referral to a urologist is indicated in those individuals with cryptorchidism. Referral for evaluation by an orthopedic surgeon in those children with congenital dislocation of the hip(s) and other joints is recommended.Spine radiographs at the time of diagnosis are indicated in all individuals with KS. If scoliosis is noted and/or vertebral abnormalities are detected, orthopedic evaluation should be considered.Obtaining T cell count, T cell subsets, and serum immunoglobulin levels in all individuals with KS at the time of diagnosis or at one year of age (whichever comes second) is recommended. An evaluation by an immunologist is indicated if the levels are abnormal or if the affected individual has a history of recurrent infections.Medical genetics consultation is appropriate.Comprehensive management guidelines are also available from DYSCERNE. See (pdf).Treatment of ManifestationsThickened feedings and appropriate positioning after meals may improve reflux symptoms.Gastrostomy tube placement is typically considered in those with severe feeding difficulties, especially if a poorly coordinated suck and swallow are noted.Thorough psychoeducational testing is indicated for all children who exhibit cognitive difficulties in order to determine strengths and weaknesses and to tailor special education services. Special education services are tailored to address strengths and weaknesses for each child with KS since no characteristic pattern of disabilities has been identified.Formal evaluation by a developmental pediatrician or psychiatrist may be helpful in those children who exhibit features suggestive of autism spectrum disorders, since educational interventions may be influenced by the result. Standard antiepileptic treatment is efficacious in treating seizures in individuals with KS. Evidence of sensorineural hearing loss is typically followed up with referral to an otorhinolaryngologist and imaging to screen for inner ear anomalies. Persistent, unexplained head and neck pain or other evidence of intracranial abnormality could be secondary to Chiari I malformation and is a clear indication for brain imaging in affected individuals. Monitoring for nocturnal lagophthalmos by parents or caregivers is recommended. If present, evaluation by an ophthalmologist is indicated.A dental evaluation as a toddler is indicated in every child with KS. Referral for orthodontic assessment should be arranged if abnormalities such as hypodontia or significant malocclusion are noted at any point in childhood. Individuals with documented immunoglobulin deficiency may benefit from scheduled intravenous immunoglobulin infusions.Treatment of premature thelarche is not warranted unless other signs of premature puberty are apparent.At least one individual has shown no change in linear rate of growth when treated with human growth hormone [Kawame et al 1999].Prevention of Secondary ComplicationsAs with many cases of congenital heart disease, prophylactic antibiotic treatment may be indicated prior to and during any procedure (e.g., dental work) that could lead to bacteremia.SurveillanceThe following are recommended for individuals with KS:Frequent monitoring of height, weight, and head circumference (at each well-child visit and, at a minimum, yearly) Evaluation of developmental milestones at each well child visit; referral for formal developmental evaluation if delays are identifiedFollowing prepubertal girls expectantly for possible premature thelarche, so that the healthcare provider can reassure parents if this finding becomes apparent Annual monitoring of visionAnnual hearing evaluationExpectant monitoring for otitis media in children. An ear examination is indicated at all well-child visits; prompt evaluation for all children with symptoms suggestive of otitis media. Regular follow up by an immunologist for those with abnormal immunologic studies or those who have recurrent infectionsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Kabuki Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKMT2D12q13.12Histone-lysine N-methyltransferase MLL2MLL2 homepage - Mendelian genesKMT2DKDM6AXp11.3Lysine-specific demethylase 6AUTX @ LOVDKDM6AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Kabuki Syndrome (View All in OMIM) View in own window 147920KABUKI SYNDROME 1; KABUK1 300128LYSINE-SPECIFIC DEMETHYLASE 6A; KDM6A 300867KABUKI SYNDROME 2; KABUK2 602113MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA 2; MLL2KMT2D Normal allelic variants. KMT2D is 36.3 kb in size and comprises 54 exons. It encodes a protein with 5537 amino acids.Pathologic allelic variants. The majority of mutations are nonsense and frameshift (72%), followed by missense mutations (16%), splice-site mutations (9%), and in-frame deletions/insertions (3%) [Bögershausen & Wollnik 2013, Makrythanasis et al 2013]. Mutations are distributed throughout the gene but are more prevalent in the 3’ exons. Whole-gene or exon deletions or duplications of KMT2D are rare, accounting for about 5% of cases [Banka et al 2013]. Normal gene product. MLL2 is a histone 3 lysine 4 (H3K4) N-methyltransferase, one of at least ten proteins that have been identified to specifically modify the lysine residue at the fourth amino acid position of the histone H3 protein [Kouzarides 2007]. MLL2 has a SET domain near its C terminus that is shared by yeast Set1, Drosophila Trithorax (TRX), and human MLL1 [FitzGerald & Diaz 1999]. MLL2 appears to regulate gene transcription and chromatin structure in early development [Prasad et al 1997]. It forms part of the MLL2/MLL3 complex, also known as the ASCOM complex, which is thought to regulate the beta-globin and ESR1 loci [Demers et al 2007].Abnormal gene product. In the majority of affected individuals, haploinsufficiency of MLL2 is likely the underlying basis of Kabuki syndrome.KDM6ANormal allelic variants. KDM6A is 239 kb in size, comprising 29 exons. It encodes a protein with 1401 amino acids.Pathologic allelic variants. In the six individuals with KS described to date who have been found to have mutations in KDM6A, one had a multiexon intragenic deletion, two had contiguous gene deletions involving a portion or all of KDM6A, two had nonsense mutations, and one had a 3-bp deletion [Lederer et al 2012, Miyake et al 2013].Normal gene product. KDM6A is an H3K27 demethylase. It has been proposed that one function of the ASCOM complex is to remove repressive epigenetic marks and deposit activating H3K4 methylation marks on chromatin. This then recruits RNA polymerase II complex, resulting in an activated chromatin state [Bögershausen & Wollnik 2013].Abnormal gene product. Haploinsufficiency of KDM6A is likely to be the underlying basis of Kabuki syndrome.