Introduction
Kabuki syndrome (KS) is multiple congenital anomaly malformation syndrome, first described by Niikawa et al.
1) in 1981. The original description involved any patient with mental retardation, skeletal and auditory anomalies, cardiac defect, and distinctive facial appearance to the traditional make-up used by Japanese actors in the Kabuki theatre
1,2). The cardinal features of KS include characteristic face, skeletal abnormalities, and dermatographic abnormalities, mental retardation, and postnatal growth deficiency
3).
KS is rare disease. The prevalence of KS in the Japanese population is estimated as 1 in 32,000
3). To date, this syndrome has been underdiagnosed outside of Japan. With increasing recognition of KS, reports of KS in various ethnicities have emerged
4).
The molecular cause of KS had been unknown for a long time. Recently pathogenic variant in KMT2D and KDM6A were identified as the causative gene in KS. However the underlying genetic cause remained undiscovered in approximately 30% of KS patients.
KS is usually diagnosed by clinical findings, but early diagnosis is difficult, because typical characteristic face of KS is vague in neonate. Diagnosis can be delayed in children with congenital heart disease (CHD) who have typical Kabuki features due to lack of physician's knowledge about KS. In many cases, patients were misdiagnosed any other syndrome like Noonan syndrome, Turner syndrome, and Van der Woude syndrome. The relationship between KS and CHD is relatively well known. However, it is uncertain that which type of cardiac anomalies is frequently associated with KS.
This study was performed to analyze clinical features and cardiac defect and to investigate the predominant type of congenital cardiac anomalies in Korean KS in a single tertiary center.
Materials and methods
Between 2002 and 2014, 13 patients were clinically diagnosed as KS in our hospital. Each patient was evaluated by a clinical geneticist or cardiologists. The diagnosis of KS was based on the presence of characteristic facial configurations, skeletal anomalies, developmental delay, and anomalies of other organs. We retrospectively reviewed the medical records, laboratory studies, surgical notes, and genetic reports performed on each patient. Cardiac evaluation included echocardiography, electrocardiogram, chest x-ray, computed tomography, cardiac catheterization and angiography. Written informed consent was obtained from all participants or their parents before identifiable blood samplings for genetic studies. The study was approved by the Institutional Review Boards of Seoul National University Hospital (IRB No. 1404-115-575).
The data are expressed as median and range. Statistical analysis was performed with IBM SPSS Statistics ver. 19.0 (IBM Co., Armonk, NY, USA). Statistical significance of the relationship between growth retardation and KS was analyzed using Wilcoxon signed-rank test. And the statistical analysis of hypoplastic left heart syndrome (HLHS) as risk factor for death was tested using the Fisher exact test. P values of <0.05 were considered statistically significant.
Discussion
KS is a multiple malformation/mental retardation syndrome
4). It is well known that CHD are frequently accompanied by KS. The prevalence of CHD with KS varies widely from approximately 28% to 80%
8). Shunt lesions or conotruncal abnormalities such as tetralogy of Fallot with KS have been in early series and left sided anomaly including HLHS with KS was more recently described
8,9,10,11). Although the various types of CHDs are well described for patients with KS, the dominant type of cardiac defects may be underestimated. It was the objective of this study to investigate the dominant type of CHD in KS.
In our series, CHD was present in 9 of 13 (69%), and all 9 had left-sided anomaly. Compared with the prevalence of heart anomalies in the previous studies conducted in Atlata
6), the incidence in our series is much higher than in the normal population, with left-sided obstruction in 7% of patients, and HLHS in 2.1%. Similarly, the prevalence of left side heart disease in our study was higher than general Korean populations of prior studies in Jeju island in 3.1% (8/236)
5).
The strong association of left-sided anomaly with KS was found in the current study. The previous study reported that CHD was present in 58% of 60 KS patients. CoA (22.8%) and septal defects (37%), such as atrial septal defect or ventricular septal defect were the most common type of CHD. Left-sided anomalies were evident in 28.5% of total KS patients with CHD
8). Another report showed the prevalence of left-sided obstructions with KS was 31%, which was significantly higher than that of general population (14%)
12). According to analysis of 121 patients with KS, CHD was present in 71 of 121 (59%) with KS. Of them, left-sided obstruction was present in 27 of 171 (38%) (
Fig. 1)
11).
Recently, the genetic studies of KS have been conducted towards causative gene mutations. In 2010,
KMT2D (previously known as MLL
2) at 12q13.12 was identified as the first gene associated with KS to be identified. Since then, 55% to 65% of KS cases have been reported to harbor the mutations in
KMT2D13).
KMT2D gene encodes a histone-3 lysine-4 specific methyltransferase (H3K4), that belongs to the SET1 family of histone methyltransferases (HMTs). H3K4 activates multiple genes that are important for embryogenesis, development, and cell differentiation
14). H3K4 is part of a large protein complex called ASCOM, which is a transcriptional regulator of estrogen receptor genes
15). Deregulated estrogen receptor mediated pathways are associated with a large spectrum of KS phenotypes, including cardiac anomalies
16). H3K4 also acts with other proteins that, includes Wdr5, Rbbp5, Ash2l, and the histone-3 lysine-27 demethylase (H3K27) (encoded by
KDM6A). Several studies have reported that
KMT2D mutations are involved in genetic diseases, such as KS or cancers, such as medulloblastoma and, myeloma. Notably, a recent study has shown that
KMT2D is involved in the control of proliferation and differentiation in mouse embryonic stem cells, particularly in cardiac-specific lineages
17).
In 2012, a
de novo deletion mutation and point mutations in
KDM6A (previously known as UTx), which is located at Xp11.3, were identified as also being involved in KS
18). From among KS patients without a
KMT2D mutation, 9% to 13% had a mutation in
KDM6A7).
KDM6A encodes the H3K27, a JmjC domain containing protein, that plays a crucial role in cell proliferation and antagonizes polycomb group-mediated repression.
KDM6A also functions in the ALR complex together with the product of
KMT2D19). In recent studies,
KDM6A knockdown fish exhibited craniofacial anomalies, including cleft palate
20). In addition,
KDM6A-deficient mice had severe heart defects
21).
KDM6A also affects the expression of key regulatory genes involved in adipogenesis and osteogenesis
22). These observations support the hypothesis that regulatory pathways by
KDM6A play an important role in KS.
Total 10 patients received genetic assay in our series. 9 of them were confirmed to have a
KMT2D gene mutation.
KMT2D and
KDM6A mutations were absent in only a single patient. Five patients had been reported in the previous publication by Cheon et al.
7). A recent report described that, 20% to 45% of KS patients remains unknown concerning the genetic basis of the syndrome
18).
The increasingly recognized role of genetic factors in the etiology of CHDs has been shown by the high frequency of heart anomalies in genetic syndromes
23). The correlation between cardiac anatomies and some genetic anomalies indicates that specific morphogenetic mechanisms set in motion by genetic mutations can result in specific cardiac phenotypes. Chromosomal anomaly or genetic syndrome with CHD can be considered an important staple resource for gene identification involved in cardiac morphogenesis
23).
A typical example of the link between a genetic syndrome and CHDs is Turner syndrome. A large proportion of patients with Turner syndrome have CoA and bicuspid aortic valve. Turner syndrome is well known in subjects with monosomy X
10). Sex chromosome anomalies have been observed in several KS patients, before the causative genes have been identified. In particular, features resembling KS were reported in a female patient with a ring X chromosome
24). In addition, in previous studies of KS patients, left-sided heart anomalies, including CoA, were found predominantly in males
8). Taken together, these observations indicate that, X-linked genetic factors may be involved in determining cardiac defects in some patients
8,25). Notably CoA and left-sided anomalies were observed predominantly in males in the normal population. It is supporting the hypothesis that the presence of two X chromosome can prevent left-sided heart anomalies
8,23). Additional evidence supporting this hypothesis is the fact that
KDM6A, one of the causative genes for KS, is located on the X chromosome (Xp11.2)
16). If the association of KS with left-sided heart anomalies is found to be significant and the genetic cause of KS is clearly revealed, we will obtain abundant knowledge about the mechanisms of cardiac development via the molecular study of this disease.
Nevertheless, a multifactorial mechanism is still remained in the etiology of left-sided anomalies. In our series, there was no male preponderance of left-sided obstruction lesion. But, this may have reflected that the small number of our series and the smaller proportion of KDM6A mutations in KS. In our study, we detected hypoplastic left heart anomaly is a high proportion of KS with CHD. There are needs to more molecular studies supporting mechanism of the high association between left-sided heart defect and KS. Authors agree that the data may be biased because this is a small series study of KS from a tertiary hospital. Our center is one of the major referral hospital for complex CHD, therefore the most severe form of cardiac malformation, such as HLHS, may be found more frequently.
The probability of long-term survival is partly determined by the presence of heart problems in KS patient. In this study, HLHS was the risk factor for death of KS. Most left-sided obstructive lesions have high mortality unless surgical correction in neonate. With the evolving surgical technique, the survival rate improved.
We believe that KS has been under-detected due to difficulties in early diagnosis and lack of molecular genetic analysis. Because cardiovascular presentation may be the earliest and the most obvious manifestation, the cardiologists are frequently the first physicians for KS patients. Therefore, pediatric cardiologist should have knowledge of KS and need to evaluate carefully about possibility of KS. Also they should be aware of high prevalence of left heart anomaly with KS, because cardiovascular presentation can be the first and the severe manifestation. On the other hand, the patients with clinical manifestation of KS are necessary for cardiac evaluation with echocardiography. It is suggested that genetic and developmental background related to cardiac malformation and KS may be clarified for prevention, further management and counseling.