Kabuki Syndrome

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Kabuki syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of KMT2D and KDM6A detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.

• Perform sequence analysis of KMT2D first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• Sequence analysis and gene-targeted deletion/duplication analysis of KDM6A can be considered next if no pathogenic variant is found.

Note: Affected individuals with classic features who have a mosaic heterozygous pathogenic variant in KMT2D have been reported; therefore, Lepri et al [2017] suggested that targeted next-generation sequencing may be a more appropriate method of mutation detection compared to traditional Sanger sequencing.

A multigene panel that includes KMT2D, KDM6A, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Kabuki syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Growth

Individuals with KS typically exhibit normal growth parameters at birth.

• Infants with KS frequently exhibit failure to thrive for a variety of reasons (see Gastrointestinal).
• In adolescence and adulthood, more than half of individuals with KS develop obesity [Cheon & Ko 2015], which can exacerbate other health problems, such as recurrent patellar dislocation (see Musculoskeletal).
• Without treatment (see Endocrine, Short stature), postnatal growth deficiency is evident by age 12 months. Lack of a typical growth spurt during puberty exacerbates short stature [Schott et al 2016a]. Microcephaly may or may not accompany short stature.

Ophthalmologic

Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, Marcus Gunn phenomenon (also referred to as jaw winking), and corneal abnormalities such as Peters anomaly.

• Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [Chen et al 2014, McVeigh et al 2015].
• Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [Caciolo et al 2018]. Failure to detect and treat these issues can exacerbate learning problems [Lehman et al 2017].
• As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring.

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.

Up to 50% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur and some individuals have progressive hearing loss. Inner-ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, and aqueductal enlargement have been reported. At least one individual with a clinical diagnosis of Kabuki syndrome who had profound progressive sensorineural hearing loss received a cochlear implant with a reported improvement in quality of life [Vesseur et al 2016].

Craniofacial

Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [Paik & Lim 2016]. 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 have lower lip pits [Porntaveetus et al 2018].

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. A majority of individuals with a molecularly confirmed diagnosis of KS are also found to have these characteristic facial features [Adam et al 2019].

Dental

A number of different dental anomalies in individuals with KS have been noted [Porntaveetus et al 2018]. Hypodontia is most common, with absent lateral upper incisors, absent lower incisors, ectopic upper six-year molars, and missing second premolars also being described. Abnormally shaped teeth (e.g., flathead-screwdriver-shaped appearance of the upper incisors), small teeth, widely spaced teeth, and malocclusion may also be seen.

Cardiovascular

Approximately 70% of individuals with KS have a congenital heart defect [Digilio et al 2017]. Many heart defects have been described in association with KS, but left-sided obstructive lesions, especially coarctation of the aorta, are the most common. Other defects may include (alone or in combination): septal defects, bicuspid aortic valve, mitral valve anomalies, conotruncal heart defects, and hypoplastic left heart syndrome. Hypertrophic cardiomyopathy and aortic root dilation have been occasionally reported.

Respiratory

Eventration of the diaphragm has been rarely reported [Zarate et al 2012].

Laryngeal abnormalities may pose problems with anesthesia (see Management, Treatment of Manifestations).

Gastrointestinal

Feeding difficulties are quite common (~70%) and may be related to hypotonia, poor oromotor coordination, and swallowing difficulties [Cheon & Ko 2015] that may require nasogastric or gastrostomy tube placement. Many individuals with KS have gastroesophageal reflux.

Abnormalities involving the gastrointestinal system are not common in KS; however, the following may be seen rarely:

• Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [Siminas et al 2015]
• Congenital diaphragmatic hernia and eventration of the diaphragm
• Cholestasis from a variety of causes
• Chronic diarrhea from malabsorption and/or celiac disease

Genitourinary

Renal and urinary tract anomalies are seen in more than 25% of affected individuals [Courcet et al 2013]. Common renal findings include anomalies of kidney position and ascent (single fused kidneys, crossed fused renal ectopia) and renal dysplasia; hydronephrosis is the most common urinary tract finding. Other anomalies may include ureteropelvic junction obstruction and duplication of the collecting system. Hypospadias and cryptorchidism can occur in males [Bögershausen & Wollnik 2013].

Musculoskeletal

Joint hypermobility is seen in 50%-75% of individuals with KS. 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).
• Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [Adam et al 2019].
• Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice.
• Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see Suggestive Findings).

Endocrine

Premature thelarche in girls is the most common endocrine abnormality described (16%-41%) [Banka et al 2012]. This finding does not represent premature puberty and is likely to resolve with time.

Short stature, even absent growth hormone deficiency, has responded to growth hormone therapy without exacerbating disproportion:

• In a study by Schott et al [2016a], average adult height without growth hormone therapy was between -2.99 SD (standard deviations) and -1.08 SD in males and between -5.57 and -1.47 SD in females.
• After one year of growth hormone treatment, the average height standard deviation score improved from -2.40 to -1.69 [Schott et al 2016b].
• Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth.
• After one year of growth hormone therapy, body proportions were not significantly affected.

Hyperinsulinism is likely underascertained in affected individuals and may be a presenting sign in neonates.

• Failure to recognize and treat hyperinsulinism in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues.
• It is estimated that about 1% of neonates with hyperinsulinism have a diagnosis of Kabuki syndrome [Yap et al 2019].

Other. The following findings have been described in a small subset of individuals with KS in the literature:

• Adrenal insufficiency
• Combined pituitary hormone deficiency
• Diabetes insipidus
• Frank growth hormone deficiency
• Hypothyroidism
• Primary ovarian dysfunction
• True precocious puberty

Immunologic

Immune dysfunction including both humoral immune deficiency and autoimmune disease has been described [Lindsley et al 2016]. Clinical findings in affected individuals may mimic those seen in individuals with common variable immune deficiency.

• Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [Lin et al 2015].
• Hypogammaglobulinemia and IgA deficiency are common.
• Diminished B-cell populations have also been reported [Lindsley et al 2016].
• Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [Brackmann et al 2013, Giordano et al 2014, Lindsley et al 2016].

Neurologic

Most children with KS are hypotonic and joint laxity may be a contributing factor.

• Hypotonia may contribute to significant feeding problems in infancy (see Growth). As with other conditions in which hypotonia is a feature, this finding tends to improve with age.
• Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [Liu et al 2015]. Good seizure control is generally achieved with standard anti-seizure medications.

Neuroimaging

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. Reported findings have included the following [Banka et al 2015, Liu et al 2015, Teranishi et al 2018]:

• Cerebellar and brain stem atrophy
• Dandy-walker malformation
• Delayed myelination
• Mild ventriculomegaly

Note: Prior to the identification of the genetic causes of KS, symptomatic Chiari I malformation was reported in multiple affected individuals [Ciprero et al 2005]. This specific finding has not been highlighted in recent publications on individuals with a confirmed molecular diagnosis. However, this does not preclude symptomatic Chiari I malformation as a clinical feature in individuals with molecularly confirmed KS.

Development

Intellectual disability, usually in the mild to moderate range, has been reported in a majority of individuals; however, reports of rare individuals with pathogenic variants in either KMT2D or KDM6A who have IQ levels above 70 have been published [Lederer et al 2012, Cheon et al 2014, Lederer et al 2014, Morgan et al 2015, Butcher et al 2017, Lehman et al 2017, Sakata et al 2017, Caciolo et al 2018]. Most individuals with KS are able to speak and to ambulate.

• Average IQ scores in individuals with KMT2D pathogenic variants range from the high 50s to high 60s [Lehman et al 2017, Caciolo et al 2018]. Rare case reports of affected individuals who are basically nonverbal have been published [Lindgren et al 2013, Miyake et al 2013].
• Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [Morgan et al 2015].
  • No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected.
  • Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described.
  • On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [Lehman et al 2017].
• In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication.
• An educational environment that stresses audio-verbal learning over visual learning may beneficial (see Ophthalmologic).

Behavior

Individuals with KS tend to be described as pleasant and outgoing.

• Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral problems including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [Banka et al 2015, Caciolo et al 2018].
• Autism continues to be a rare but described finding in affected individuals [Paděrová et al 2016, Sertçelik et al 2016]. Whether this is truly part of the spectrum of KS or is a coincidental secondary diagnosis due to the frequency of autism spectrum disorders in the general population remains to be seen.

Benign Tumors

Pilomatricomas, benign tumors of the hair shaft that commonly occur on the head and neck, have been described rarely in those with Kabuki syndrome [Bernier et al 2017]. In most cases, removal by a dermatologist is sufficient.

Malignancies

Although pathogenic somatic variants in KMT2D and KDM6A have been seen in a variety of sporadic tumors [Huether et al 2014], malignancies (primarily as case reports) have only been described in a few individuals with KS. There is no clear evidence of a significant predisposition to the development of cancer in individuals with KS [Roma et al 2015, Karagianni et al 2016]. Therefore, no tumor screening protocol for individuals with KS has been developed.