Kabuki Syndrome

Etiology

KSK is caused by variants in the KMT2D and KDM6A genes. Seventy-five percent of cases are secondary to either de novo or inherited pathogenic/likely pathogenic variants in KMT2D. In comparison, 5% of the cases are attributed to variants in KDM6A, which has an X-linked dominant inheritance pattern; the etiology for the remaining 20% of cases remains unknown.[4]

Epidemiology

KS has an estimated frequency of about 1 in 32,000 to 1 in 86,000 individuals.[3] Although this condition was first described in Japan in the 1980s and was initially thought to be a syndrome specific to the East Asian population, recent data does not support an increased prevalence of this syndrome in any particular ethnicity.[3][4]

Pathophysiology

The pathogenesis of Kabuki syndrome is defined by epigenetic modifications during embryogenesis that regulate the expression level of genes (mainly KMT2D and KDM6A) by the on and off switch of chromatin.[1] KMT2D protein is a histone (H3) lysine methyltransferase protein, and KDM6A is a histone demethylase protein, both with complementary functions. KMT2D protein plays a role in opening the chromatin, while KDM6A acts by closing the chromatin. The switch between open and closed chromatin states affects the transcription process, ultimately causing the disease.[4]

The KMT2D mutation affects normal growth and development by interrupting histone methylation related to gene expression. This mutated gene was the first pathogenic gene recognized in Kabuki syndrome, also known as MLL2. Recognized in 2010, this is the most common gene mutation in patients with Kabuki syndrome, found in 75% of cases.[1][4] This condition is inherited in an autosomal dominant pattern.[3] The proportion of cases caused by a de novo KMT2D mutation is unknown but is likely high.[5] The KMT2D gene is located on chromosome 12q13, which is expressed in most cells in the body. This encodes a large nucleoprotein that regulates histone methyltransferase activity, which methylates the Lys4 residue of histone H3 (H3K4). H3K4Me (methylated H3K4) activates transcriptional initiation sites on up to 75% of human genes.[1] More than 50 mutations at different sites of KMT2D have been found, including nonsense, missense, frameshift mutations, small deletions, and splice site variants.[1][3] Rare mosaic KMT2D cases have been identified.[3]

The KDM6A mutation affects normal growth and development through similar mechanisms of KMT2D, as both genes belong to the same multiprotein complex. KDM6A (also known as UTX) is the second most pathologic gene, found in less than 5% of patients with Kabuki syndrome.[1] This mutation is inherited in an X-linked manner; the gene is located on Xp11.23 and encodes a histone (H3)-lysine 27-specific demethylase that interacts with KMT2D in regulating gene expression in the activating signal cointegrator-2-containing complex (ASCOM).[1][3][5] Mutations of KDM6A include nonsense, frameshift, splice site, missense, large deletions, small insertions, and small deletions; a rare mosaic case of KDM6A has previously been identified.[3]

The penetrance of pathogenic variants in KMT2D is not complete. The penetrance is unknown for pathogenic variants of KDM6A. Given the variable expressivity, patients with a mild phenotype may remain undiagnosed.[5] Genetic defects remain unknown in about 20% of patients with KS.[1][4] Patients without KMT2D or KDM6A mutations are often referred to as having Kabuki-like syndrome. Proband mutations suggestive of Kabuki-like syndrome are found in the HNRNPK gene. Reported copy number variations associated with Kabuki-like syndrome include MACROD2 gene microdeletion and 8p22-p23.1 duplication. Mutations in KDM1A, RAP1A, and RAP1B have also been implicated; other genes associated with a Kabuki-like phenotype likely exist.[1][3]

History and Physical

KS derives its name from the distinct dysmorphic facial features resembling traditional Japanese 'Kabuki' theatre actors. The characteristic facial gestalt includes long palpebral fissures, eversion of the lateral third of the lower eyelid, arched and broad eyebrows with sparse lateral third brows, depressed nasal tip, and prominent or cupped ears.[1][3] As outlined, the 2 main genes responsible are KMT2D and KDM6A. Based on the underlying genotype, there can be 2 slightly different phenotypes described below. Heterozygous pathogenic variants in KMT2D lead to more characteristic clinical features of Kabuki syndrome, known as Kabuki type 1 (KS1). Heterozygous or hemizygous pathogenic variants of KDM6A are responsible for Kabuki type 2 (KS2).[1][3] Patients who share similar facial dysmorphisms but do not have mutations in either of the genes are described as having KS-like syndrome.[1]

The most commonly reported cardinal features include the following: 

• Facial dysmorphism 
• Skeletal anomalies 
• Dermatoglyphic anomalies 
• Variable intellectual disability
• Impaired growth

However, KS is now widely recognized as a more variable phenotype involving multiple organ systems.[3]

Craniofacial

Distinct craniofacial abnormalities, including long palpebral fissures with eversion of the lateral third of the lower eyelids, high arched eyebrows with notching or sparseness of the lateral third eyebrow, and depressed nasal tip with short columella are present in almost all individuals with Kabuki syndrome.[1][5] Thick eyelashes, flattening of the nose, thinning of the upper lip, thickening of the lower lip, and a large or tented area between the nose and mouth are also characteristic.[4][6] External ear abnormalities include large or prominent ears, cupping of the ears, and ear pits. Midface and mandibular hypoplasia have been reported.[4] Cleft lip and cleft palate affect one-third of patients with KS. Other palatal abnormalities, such as a high-arched palate, are also common, leading to frequent otitis media, feeding difficulties, and speech difficulties.[5]

Hearing loss is common in patients with Kabuki syndrome. Up to 50% of patients have hearing loss, often due to chronic otitis media, but may also be due to inner-ear malformations such as vestibular enlargement, Mondini dysplasia, aqueductal enlargement, aplastic cochlea, and semicircular canals.[5] More severe external abnormalities, such as microtia and preauricular fistula, have also been reported.[4] Dysmorphic facial features are less apparent in neonates, infants, and adults but are most commonly noticeable in early childhood between 3 and 12 years of age.[3]

Cardiovascular

Approximately 70% of all patients with KS have congenital heart disease.[5] The prevalence is higher in those with KMT2D gene mutations, affecting up to 80% of patients.[1][4] Many types of congenital heart defects are found to be associated with this syndrome, however, atrial septal defect, ventricular septal defect, and left-sided obstructive lesions such as coarctation of the aorta are the most common.[5][4] Nearly half of all patients with KMT2D mutations and congenital heart disease will have aortic coarctation or septal defects. Juxtaductal coarctation of the aorta is the most common type of coarctation of the aorta in patients with Kabuki syndrome and has been identified as a cardinal feature of the syndrome.[4] Less than half of individuals with Kabuki syndrome have this condition due to a KDM6A variant present with congenital heart disease. Of those who do, most have right-sided heart defects.[4]

Other congenital heart defects include pulmonary stenosis, mitral valve anomalies, bicuspid aortic valve, conotruncal defects, tetralogy of Fallot, transposition of the great vessels, double-outlet right ventricle, Ebstein anomaly, hypoplastic left heart syndrome, hypertrophic cardiomyopathy, and aortic root dilation.[5][4] There are rare reports of patients with Kabuki syndrome presenting with arrhythmias, but research on conduction abnormalities in these patients is lacking.[4] Individuals with KS have an increased risk of hypertension secondary to premature atherosclerosis.[3] Systemic vascular abnormalities have also been noted, which may increase the risk of stroke and ischemic disease.[4]

Pulmonary

There are few reports of lung manifestations in patients with KS.[7] Respiratory problems may be due to recurrent aspiration from feeding issues, leading to oxygen-dependent chronic lung disease from aspiration pneumonia.[4] Interstitial lung disease, eventration of the diaphragm, congenital diaphragmatic hernia, and pulmonary hypertension have been reported.[5][7]

Gastrointestinal

Feeding difficulties are common in up to 70% of individuals with Kabuki syndrome. Feeding difficulties are related to poor oromotor coordination, cleft lip/palate, problems with swallowing, and hypotonia. These feeding difficulties may lead to poor nutrition and failure to thrive, resulting in poor growth.[5] Feeding difficulties due to poor oromotor coordination may also lead to aspiration events.[4] Nasogastric or gastrostomy tube placement may be indicated in 65% to 75% of patients.[4] 

Other gastrointestinal manifestations include gastroesophageal reflux disease, esophageal or gastric polyps, chronic diarrhea secondary to malabsorption, celiac disease, intestinal malrotation, pancreatic duct abnormalities leading to pancreatitis, and hepatobiliary tract abnormalities including biliary atresia, hepatic fibrosis and cholangitis, and neonatal cholestasis. Anorectal malformations, including imperforate anus, anterior anus, perineal fistula, and rectovestibular fistula, are also known to be associated with Kabuki syndrome.[1][5]

Renal and Genitourinary

Renal and genitourinary anomalies are found in over 25% of patients with Kabuki syndrome.[5] Renal anomalies are often due to abnormal position and ascent of the kidneys, leading to single-fused kidneys, renal dysplasia, and crossed-fused renal ectopia. Hydronephrosis is the most common renal anomaly. Ureteropelvic junction obstruction, duplication of the renal collecting system, horseshoe kidney, ureteral duplication, and renal insufficiency are other known associations.[1][5][4] Genitourinary anomalies include cryptorchidism and hypospadias in males and hypoplastic labia in females.[3][5] Data are lacking regarding reproductive health and fertility in those with Kabuki syndrome.[3]

Growth

Growth restriction in childhood affects 60% to 83% of patients with KS.[3] Weight and length are usually normal at birth, with the growth delay starting in the first year of life. Patients with a KMT2D pathogenic variant demonstrate growth patterns about 2 standard deviations below the norm, with short stature present in 75% of the patients.[4] Additionally, these patients lack a growth spurt during puberty.[5] Children with Kabuki syndrome will often have larger heads and longer arms in proportion to the rest of their body.[5] Although growth restriction is present in early childhood, up to 57% of patients will develop obesity after the age of 5.[4]

Endocrinologic

Hypoglycemia presents in up to 28% of patients with Kabuki syndrome in either the neonatal period or later in life.[8] Persistent hypoglycemia may occur in neonates due to hyperinsulinism and may be a presenting sign of the syndrome. There is an estimation that approximately 1% of neonates with hyperinsulinism have KS.[5] Patients with KDM6A mutations have an increased risk of hyperinsulinemic hypoglycemia due to the effect of KDM6A on insulin release from beta-cells of the pancreas.[8] 

Individuals with this condition may also present with other abnormalities of the endocrine system, such as precocious puberty, delayed sexual development, diabetes insipidus, diabetes mellitus type II, adrenal insufficiency, hypothyroidism, and primary ovarian dysfunction.[1][3][5] Isolated premature thelarche is seen in up to 40% of girls with KS and is not indicative of premature puberty as it usually resolves with time.[5]

Neurologic

KMT2D gene mutations affect the development of the nervous system as the gene plays a role in regulating adhesion-related cytoskeleton processes and neuronal differentiation. Neurological manifestations of KS include hypotonia, feeding difficulties, sensorineural hearing loss, chorea, microcephaly, psychomotor delay, and neurobehavioral abnormalities.[1][4] Hypotonia is highly prevalent and affects 51% to 98% of patients with this syndrome.[3] Seizures are common, affecting up to 40% of individuals. A wide range of seizure types have been described, including infantile spasms. Control of seizures is usually achieved with standard anti-epileptic regimens.[5] Those with Kabuki syndrome usually have normal brain imaging, although structural lesions such as Dandy-Walker malformation, mild ventriculomegaly, thinning of the pituitary, delayed myelination, and atrophy of the cerebellum and brain stem have been reported.[1][5][9] 

Ocular

Ocular manifestations occur in 38% to 72% of patients with KS and may include blue sclerae, ptosis, strabismus, amblyopia, refractive error, Peters anomaly of the cornea, coloboma, optic disc anomalies, nystagmus, and Marcus Gunn phenomenon.[1][3][5] The everted lower eyelid can cause excessive tearing and nocturnal lagophthalmos. Nocturnal lagophthalmos can lead to blepharitis, corneal abrasion, and scarring. Difficulties with functional vision may be due to problems with visuoperception, motor coordination, and visuomotor integration. More severe anomalies such as anophthalmia, microphthalmia, and optic nerve hypoplasia may occur.[5]

Cognitive

Mild to moderate intellectual disability affects most patients with Kabuki syndrome.[5] This is partly due to a deficiency in postnatal neurogenesis as a direct result of the KMT2D mutation, suggesting a neural basis for cognitive and intellectual impairment.[4] Average intelligence quotient (IQ) scores with KMT2D pathogenic variants have been reported to be in the high 50s to high 60s, although individuals with a more severe disability may be nonverbal. Severe intellectual disabilities may be found in patients with truncating variants in the first half of KMT2D or those with a whole deletion of KMT2D. Rare pathogenic variants of KMT2D and KDM6A have reported IQ levels above 70.[5]

Patients with KS often have hypophrenia, presenting with varying degrees of language and optomotor deficits. The most common deficit is dysarthria, characterized by poor sound quality, hypernasality, tone distortion, and inaccurate consonants. Most patients demonstrate a decline in the ability to understand and express language. Verbal Comprehension Index (VCI) and Full Scale Intellectual Quotient (FSIQ) scores of patients with KMT2D mutations were found to be 10 points lower when compared to other mutation types.[1] 

Psychiatric

Autism spectrum disorder and attention-deficit hyperactivity disorder may affect a subset of individuals. Patients with Kabuki syndrome are typically described as pleasant and social, although anxiety disorder and self-harm behaviors have been reported.[5] Results from a recent study found that over one-third of children with KS and 80% of adults with KS are treated for anxiety or scored high enough to qualify for an anxiety disorder diagnosis. This data did not correlate with cognitive ability or adaptive function, suggesting that anxiety may be a prevalent phenotype in Kabuki syndrome regardless of intellectual ability or environmental factors.[10] Sleep disorders are also thought to be a common manifestation of this condition.[11]

Development

Delays in developmental milestones are often present in children with Kabuki syndrome. Intellectual disability, hypotonia, congenital heart defects, and hearing loss can cause delays in speech, language, and motor development; this can lead to difficulties with feeding, sitting, walking, and toilet training.[3] A study examining the acquisition of milestones found that sitting unassisted occurred at 11 months, walking unassisted occurred at 20 months, and the first spoken word occurred at 21 months.[12] Language development varies in patients with KS. Although most children eventually develop the skills to speak in complete sentences, some patients may not develop the ability to utilize single words or sentences until they are 10 or older, and some patients may remain nonverbal.[3]

Musculoskeletal and Dermatologic

Musculoskeletal abnormalities are common in patients with this condition, affecting 50% to 75% of individuals. Joint laxity is a common finding leading to joint dislocations, especially of the hips, shoulders, and knees. Skeletal anomalies in Kabuki syndrome include premature hyperplasia of the sagittal and coronal sutures leading to facial asymmetry, interrupted clavicle, clinodactyly of the fifth digit, brachydactyly and brachymesophalangy.[5] Various spinal abnormalities are associated with KS, including scoliosis, butterfly vertebrae, sagittal clefts, hemivertebrae, and narrow intervertebral disc space.[5] Dermatoglyphic manifestations include prominent digit or persistent fetal finger pads.[1][5] Dental anomalies include hypodontia, abnormally shaped teeth, small teeth, and widely spaced teeth.[5]

Immunologic

Immune deficiency disorders and autoimmune disorders are found in 60% to 73% of patients with Kabuki syndrome.[3] KMT2D mutations interfere with the differentiation of terminal B-cells, causing problems with the humoral immune response and autoimmunity. Thus, individuals with KS often have a loss of memory cells, lack antibodies, and have a poor response to vaccines. Most patients will have hypogammaglobulinemia with immunoglobulin (Ig)A deficiency, although hyper-IgM syndrome and common variable immunodeficiency are also possible.[1] Decreased B-cells and frequent and recurrent infections (namely otitis media and sinopulmonary infections. have been reported[5]. Autoimmune diseases, including vitiligo, thyroiditis, hemolytic anemia, and idiopathic thrombocytopenia purpura) have also been reportedal.[1][5] 

Oncologic

KMT2D's involvement in malignancy is characterized by its regulation of cell differentiation and tumor suppression, making it one of the most prevalent mutations found in gastric cancer, medulloblastoma, and lymphoma.[1] Somatic variants in KDM6A have been described in T-cell acute lymphoblastic leukemia, urothelial carcinoma, and breast cancer.[5] Pilomatricomas, benign tumors of the hair shaft often affecting the head and neck, have also been described in individuals with Kabuki syndrome.[5] Other known associations include spinal ependymomas and giant cell fibroblastomas. Although malignancies have been described, there is no clear evidence of increased predisposition to the development of malignancy in patients with this condition and thus, no current tumor screening protocol exists.[3][5] More work needs to be done to better elucidate the relationship between KS and malignancy.[1]

Prenatal

Information on prenatal and perinatal complications of Kabuki syndrome is lacking. There have been reports of abnormal second and third-trimester ultrasounds in 69% of patients and abnormal quad screens in 44% of patients. Polyhydramnios has been reported in 25% to 41% of pregnancies with fetuses affected by KS, which may be due to impairment of swallowing or craniofacial abnormalities.[13] No specific feature found on fetal ultrasound has a high positive predictive value for Kabuki syndrome. However, the diagnosis should be considered in a fetus with congenital anomalies, polyhydramnios, and regular karyotype/microarray testing.[14]

Differences in Phenotype

Patients with KS1 (those with the KMT2D pathogenic variant) are more likely to have the distinctive facial phenotype of Kabuki syndrome. These patients are also more likely to have feeding problems, palatal abnormalities, renal anomalies, joint dislocation, and premature thelarche in females.[5] They are also more likely to have congenital heart disease, specifically with left-sided obstructive lesions or septal defects.[4] 

Patients with KS2 (those with the KDM6A pathogenic variant) may be less likely to have typical facial features of Kabuki syndrome.[3] The KS2 phenotype is more likely to have hypoglycemia secondary to hyperinsulinism in infancy, short stature in the preadolescent period, hypertrichosis, large central incisors, and large halluces.[1][5] Girls with KS2 may have normal growth, with speech and cognitive ability more severely affected than motor development. Boys with KS2 are found to have more severe intellectual disability and developmental delays than girls with KS2.[1] Girls with KS2 also tend to have milder features than males with KS2.[5] Patients with KS2 are less likely to have congenital heart defects, and those who present are more likely to have right-sided lesions.[4] 

Multiple syndromes such as Wiedemann-Steiner syndrome, CHARGE syndrome, and Turner syndrome are thought to have some genotypic and phenotypic overlap with Kabuki syndrome.[1] There are also reported cases of patients with variants of KMT2D that meet genetic and clinical criteria for the diagnosis of Kabuki syndrome but who also have unusual features of KS suggestive of a new underlying disease mechanism.[15]

Evaluation

Kabuki syndrome is a challenging clinical diagnosis because many characteristics are absent in the initial neonatal period and may not become evident until later in life. Those with the KMT2D mutation are more likely to have clinical features characteristic of this syndrome in infancy compared to those with a KDM6A mutation. Multiple scoring systems have been developed to diagnose patients with KS who have not had genetic testing or who have had genetic testing with no identifiable etiology.[1]

Suspected Diagnosis

Kabuki syndrome should be suspected in patients with any combination of the 5 cardinal features defined by Niikawa et al, structural anomalies specific to KS, and functional differences found in patients with KS.

Cardinal manifestations, as defined by Niikawa et al, include the following:

• Typical facial features: long palpebral fissures with ectropion of the lateral third of the lower eyelids, high arched eyebrows with the lateral third of the eyebrow with notching or sparseness, depressed nasal tip with a short columella, large or cupped ears                                                                                                         
• Skeletal abnormalities: spine anomalies including butterfly vertebrae, narrow intervertebral disc space, scoliosis, hemivertebrae, sagittal clefts; brachydactyly, clinodactyly of the fifth digit,  brachymesophalangy                                                                                                                                   
• Dermatoglyphic abnormalities: the presence of fetal fingertip pads                                                                                                                                                                                    
• Intellectual disability                                                                                                                                        
• Postnatal growth deficiency

Structural abnormalities encompass the following:

• Ophthalmologic anomalies
• Ear pits
• Cleft lip/palate
• Dental abnormalities
• Congenital heart defects
• Gastrointestinal anomalies
• Genitourinary abnormalities

Functional abnormalities are as follows:

• Hearing loss,
• Difficulty with feeding,
• Endocrinologic abnormalities,
• Increased susceptibility to autoimmune disorders and infection
• Seizures [5]

Diagnostic Criteria

International consensus on the diagnostic criteria for Kabuki syndrome was established in 2019.[4][16] The definitive diagnosis can be made in a patient with a history of hypotonia in infancy, developmental delay with or without intellectual disability, and one or both of the following factors: genotype confirmation and/or typical dysmorphic features. Genotype confirmation includes the presence of a heterozygous pathogenic variant of KMT2D or a hemizygous or heterozygous pathogenic variant in KDM6A. Molecular gene testing can include gene-targeted testing (single-gene testing, serial single-gene testing, multigene panel) or comprehensive genomic testing (chromosomal microarray, exome array, exome sequencing, genome sequencing). Typical dysmorphic features must include long palpebral fissures (at least 2 standard deviations above the mean for age) with ectropion of the lateral third of the lower eyelid and at least 2 of the following characteristic features: high-arched eyebrows with notching or sparseness of the lateral third eyebrow, depressed nasal tip with short columella, large or cupped ears, and persistent fetal fingertip pads). The typical dysmorphic features must only be present at some point in life to qualify for the diagnosis.[5][16]

Genetic Testing

Genetic testing can be approached in 2 ways. When phenotypic findings suggest a diagnosis of Kabuki syndrome, genetic testing can include either single-gene testing or a multigene panel. Single gene testing with sequence analysis will detect missense, nonsense, splice site variants, and intragenic insertions/deletions.[5] Some specialists recommended that sequence analysis of KMT2D be performed first. If no pathogenic variants are found, performing gene-targeted deletion/duplication analysis is recommended. If no pathogenic variant is found, both sequence analysis and gene-targeted deletion/duplication analysis should be performed on KDM6A. Alternatively, a multigene panel that includes KMT2D, KDM6A, and other genes of interest can help identify a pathogenic variant while limiting variants of uncertain significance and pathogenic variants not explained by the underlying phenotype. In patients with KMT2D pathogenic variants, >99% were detectable by sequence analysis. In patients found to have KDM6A pathogenic variants, approximately 80% were detected with sequence analysis, and approximately 20% were detected with gene-targeted deletion/duplication analysis.[5]

When phenotypic findings do not suggest a diagnosis of KS, comprehensive genomic testing should be performed with either exome sequencing or genome sequencing. Disorder-specific genome-wide changes in deoxyribonucleic acid methylation profiles are found in peripheral blood leukocytes in patients with KS This approach to diagnosis can be considered in patients who have phenotypic findings suggestive of Kabuki syndrome but in whom no pathogenic variant has been found in KMT2D or KDM6A or in patients with phenotypic findings suggestive of KS who have had a KMT2D or KDM6A variant of uncertain significance identified.[5]

Treatment / Management

Treatment of individuals with Kabuki syndrome is limited to the management of clinical manifestations, prevention of secondary complications, and surveillance.[1]

Management of Clinical Manifestations

Due to this condition affevting multiple organs, caring for patients requires involvement from multiple subspecialists. While most abnormalities require medical therapy and ongoing surveillance, involvement of the cardiovascular system and congenital structural heart defects may require surgery. Hypoplastic left heart syndrome and coarctation of the aorta are among the most common cardiac defects that need surgical repair in the results of a study.[17] Feeding difficulties should be managed with thickened feeds; if severe, placing a gastrostomy tube may be recommended. A feeding team should be involved with the patient’s care.[1][5] Gastrointestinal issues such as gastroesophageal reflux disease and chronic diarrhea should be managed in conjunction with a gastroenterologist.

Hearing loss may require pressure-equalizing tubes or hearing aids. Cleft and palatal abnormalities will require repair with a craniofacial team. Genitourinary abnormalities should be managed by a nephrologist and urologist and may require surgical repair. Recurrent infections may require expertise with immunologic specialists with consideration of immunoglobulin therapy in those with immunoglobulin deficiency. Seizure disorders should be managed with anti-seizure medications and oversight from a neurologist.[5] 

Short stature should be managed with consultation with an endocrinologist, and growth hormone should be considered. Although Kabuki syndrome is not associated with growth hormone deficiency, growth hormone therapy may be considered in those who are deficient.[4] Data are limited on the effect of human growth hormone therapy, although results from small studies have shown an improvement in linear growth.[3] Growth hormone therapy may worsen tumor burden, and these risks should be considered carefully given the possible increased risk of malignancy in patients with KS.[5]

Referral to an early intervention program is recommended for patients who are 3 and younger, and an individualized education program is recommended for school-aged children. Physical therapy, occupational therapy, and speech therapy are recommended for patients with Kabuki syndrome.[5] Anesthesia specialists should be aware of potential airway abnormalities that can make intubation difficult and should be cautious during patient positioning, given the joint laxity of the cervical spine.[5]

Surveillance

Surveillance includes monitoring growth, developmental milestones, hearing, and vision at each well-child visit.[5] Normative growth curves designed for children with Kabuki syndrome should be utilized if possible.[4] Patients with abnormal growth velocity should be assessed for hypothyroidism and growth hormone deficiency. Scoliosis should be evaluated yearly until skeletal maturity is achieved. Patients should have thyroid function tests and a complete blood count every 2 to 3 years.[5]

All patients should have a baseline ophthalmology exam to assess for ophthalmologic issues such as strabismus, refractive abnormalities, corneal abnormalities, and ptosis. All patients should have a baseline echocardiogram to look for congenital heart defects. Chest radiographs should be considered to assess for diaphragmatic eventration in patients with respiratory problems, recurrent pneumonia, or chronic cough. A feeding team should be involved to assess for feeding difficulties. The mouth should be assessed for palatal abnormalities. A baseline renal ultrasound should be obtained to look for renal anomalies and a genitourinary exam should be performed to evaluate for abnormalities such as cryptorchidism and hypospadias A radiograph of the spine in patients with scoliosis should be obtained to assess for vertebral anomalies. Given the association with immunodeficiency, patients should have a T-cell count, T-cell subsets, and serum immunoglobulin levels at diagnosis or by 1 year of age. An echoencephalogram should be obtained for any patients with suspected seizures, and brain magnetic resonance imaging can be considered to evaluate for structural abnormalities.[5]

Neuropsychiatric and developmental assessments should be completed to assess for speech, cognitive, and motor skills as well as assess for attention-deficit hyperactivity disorder and autism spectrum disorder. Dental evaluation should be considered for patients 3 years of age or older. Patients should be referred to otolaryngology, craniofacial, ophthalmology, cardiology, pulmonary, gastrointestinal, surgery, orthopedic, endocrine, neurology, orthopedic, nephrology, urology, and dental specialists as indicated. Consultation with a geneticist or genetic counselor is also recommended.[5]

Alternative Treatment

Therapies currently under investigation for patients with Kabuki syndrome include histone deacetylase inhibitors and a ketogenic diet. Currently, these therapies are not recommended, as evidence is insufficient.[5]

Differential Diagnosis

The differential diagnosis for Kabuki syndrome includes disorders that have overlapping clinical features, including the following:

• CHARGE syndrome has similar features, such as cleft palate, congenital heart disease, coloboma, and growth restriction, but this condition can be differentiated from KS typical by facial features, such as a square face and short/wide ears.

• 22q11.2 deletion syndrome shares features with KS, such as cleft palate, congenital heart disease, and renal abnormalities, but differs from Kabuki syndrome in that palpebral fissures are short and narrow, and ears are small and C-shaped. IRF6-related disorders have similar features, such as cleft lip/palate and lip pits, but these disorders are not typically associated with abnormal growth and development, typical KS facial features, or cardiac anomalies.

• Brachio-oto-renal syndrome can present with ear pits, cupped ears, hearing loss, and renal anomalies, but patients otherwise have normal facial features and normal growth and development.

• Hypermobile Ehlers-Danlos syndrome and Larsen syndrome share similar features with KS, such as joint hypermobility and blue sclerae; however, these disorders are not associated with anomalies of other organ systems.

• Hardikar syndrome may present similarly to KS, given prolonged hyperbilirubinemia and cleft lip/palate, but patients with KS do not typically develop sclerosing cholangitis, which is seen in Hardikar syndrome.

Other chromosomal abnormalities may present with similar facial features of Kabuki syndrome, congenital heart defects, and growth restriction. However, these syndromes can be differentiated from KS with chromosomal microarray or chromosome analysis.[5]

Prognosis

Kabuki syndrome is a relatively new diagnosis (the first diagnosis was made in the early 1980s); data are lacking on long-term outcomes. Most patients with KS will live into adulthood.[6] However, the prognosis of patients with KS varies, given the heterogeneity of the syndrome. Prevention and management of complications play a key role in improving prognosis.[4]

Complications

Multisystem complications are possible in patients with KS. These diverse complications necessitate a multidisciplinary approach to management and ongoing monitoring. Early recognition of issues is imperative for preventing complications.[4]