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The long palpebral ¢ssures, everted lower eyelids and ptosis of the eyelids, reminiscent of Kabuki theatre actors are almost pathognomic for the KS (upper left and right), certainly if combined with fetal pads (lower left). The large ears with hypoplastic antihelices and depressed nasal tip are also typical ¢ndings (upper right). Short stature is also a frequent ¢nding (lower right).
Source publication
The Kabuki (make-up) syndrome identified in 1981 has been reported in more than three hundred patients. Typical findings include 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, skeletal and visceral...
Context in source publication
Citations
... Kabuki syndrome patients develop a myriad of multi-organ deficiencies that manifest in a variety of clinical features. In craniofacial tissues, Kabuki patients exhibit facial hypoplasia that produces a broad, depressed nasal tip that can be accompanied with cleft or high-arched palate, high-arched eyebrows, elongated palpebral fissures, lower eyelid eversion, prominent ears, and micrognathia (see Figure 1a for craniofacial frequencies; Adam et al., 2019;Wessels et al., 2002;Porntaveetus et al., 2018). Craniofacial dysmorphism is accompanied by a variety of dental abnormalities including excessive caries, enamel hypoplasia, altered tooth shape, size, and agenesis (Porntaveetus et al., 2018;Teixeira et al., 2009). ...
... Craniofacial dysmorphism is accompanied by a variety of dental abnormalities including excessive caries, enamel hypoplasia, altered tooth shape, size, and agenesis (Porntaveetus et al., 2018;Teixeira et al., 2009). Irregularities in skeletal development produce short stature with reduced postnatal growth, scoliosis, hip dysplasia, joint laxity, hypermobility, and patellar dislocation (see Figure 1b for skeletal frequencies with regards to ossification origins; Adam & Hudgins, 2005;Barry et al., 2022;Bogershausen et al., 2016;Schrander-Stumpel et al., 2005;Wessels et al., 2002). Outside of craniofacial and skeletal features, alterations in other organ systems result in intellectual deficiencies, dermatoglyphic abnormalities, developmental delay, otitis media and recurrent infections, and a variety of congenital heart problems including atrial and ventricular septal defects as well as aortic coarctation (Barry et al., 2022;Bögershausen & Wollnik, 2013). ...
... (a) Frequencies of common craniofacial features found in Kabuki syndrome patients. Phenotypic frequencies in parts (a) and (b) were compiled from the following References: (Adam & Hudgins, 2005;Barry et al., 2022;Schrander-Stumpel et al., 2005;Wessels et al., 2002). (b) Illustration demonstrating frequencies of common skeletal features present in Kabuki syndrome patients with reference to mode of bone formation and cellular origin. ...
Background
Kabuki syndrome is a congenital developmental disorder that is characterized by distinctive facial gestalt and skeletal abnormalities. Although rare, the disorder shares clinical features with several related craniofacial syndromes that manifest from mutations in chromatin‐modifying enzymes. Collectively, these clinical studies underscore the crucial, concerted functions of chromatin factors in shaping developmental genome structure and driving cellular transcriptional states. Kabuki syndrome predominantly results from mutations in KMT2D, a histone H3 lysine 4 methylase, or KDM6A, a histone H3 lysine 27 demethylase.
Aims
In this review, we summarize the research efforts to model Kabuki syndrome in vivo to understand the cellular and molecular mechanisms that lead to the craniofacial and skeletal pathogenesis that defines the disorder.
Discussion
As several studies have indicated the importance of KMT2D and KDM6A function through catalytic‐independent mechanisms, we highlight noncanonical roles for these enzymes as recruitment centers for alternative chromatin and transcriptional machinery.
... Motor delay in KS patients is mainly related to infantile hypotonia and attention deficit [36]. Patients often manifest short stature due to poor feeding and nutrition, growth hormone (GH) deficiency and disrupted endochondral ossification of the long bone growth plates [37,38]. Children with KS can benefit from an endocrinological evaluation and GH treatment [3]. ...
... There is a paucity of information regarding fertility and reproductive health pertaining to KS. Familial transmission of KS both to and from affected males and females has been reported [19][20][21][22]37]. Endocrine dysregulation can interfere with fertility, but the extent and implication of this are not adequately discussed in the existing literature [116]. Both patients and clinicians would benefit from further research in this area. ...
Kabuki syndrome (KS) is a rare neuro-developmental disorder caused by variants in genes of histone modification, including KMT2D and KDM6A. This review assesses our current understanding of KS, which was originally named Niikawa–Kuroki syndrome, and aims to guide surveillance and medical care of affected individuals as well as identify gaps in knowledge and unmet patient needs. Ovid MEDLINE and EMBASE databases were searched from 1981 to 2021 to identify reports related to genotype and systems-based phenotype characterization of KS. A total of 2418 articles were retrieved, and 152 were included in this review, representing a total of 1369 individuals with KS. Genotype, phenotype, and the developmental and behavioral profile of KS are reviewed. There is a continuous clinical phenotype spectrum associated with KS with notable variability between affected individuals and an emerging genotype–phenotype correlation. The observed clinical variability may be attributable to differences in genotypes and/or unknown genetic and epigenetic factors. Clinical management is symptom oriented, fragmented, and lacks established clinical care standards. Additional research should focus on enhancing understanding of the burden of illness, the impact on quality of life, the adult phenotype, life expectancy and development of standard-of-care guidelines.
... At least 12 RDs that progress with microdontia have been identified [6]. A number of the systemic diagnoses of the patients who compose the present series have been related to microdontia, such as Kabuki syndrome [23], Williams syndrome [24], hereditary ectodermal dysplasia [25] and Zellweger syndrome [26]. Dental enamel defects, and especially hypoplasia, have been reported in 30 different RDs [6]. ...
The available literature on the orthodontic treatment of patients with rare disorders is extremely scarce. The aim of this study was to analyze the diagnosis and orthodontic treatment of a group of 94 individuals with rare diseases, referred for orthodontic evaluation to a university special care dentistry center (University of Santiago de Compostela, Spain). We created a control group of 94 systemically healthy individuals, paired by sex and age range. For all participants, we recorded their dental and skeletal abnormalities, oromotor dysfunctions and the characteristics of their orthodontic treatment. Some of the morphological and functional abnormalities were more prevalent in the rare disorders group than in the control group, including dental agenesis, microdontia, enamel defects, maxillary hypoplasia, overbite, cleft lip/palate, mouth breathing, atypical swallowing, lingual/labial interposition, labial incompetence, modified consistency diet, bruxism, and muscle tone abnormalities. Compared with the control group, the 56 patients with rare disorders who underwent orthodontic treatment required more desensitization sessions, used mixed appliances (fixed and removable) more often and for longer periods and had more frequent complications, such as gingivitis, caries, mucosal ulcers and recurrent debonding of the device. In conclusion, for selected patients with rare disorders, it is feasible to perform orthodontic treatment, whose planning will be determined by the dental-skeletal abnormalities and oromotor dysfunctions. Although complications are more frequent, they can typically be solved without having to stop treatment.
... The most frequent ophthalmologic anomaly reported in literature is strabismus (36%) [20][21][22][23][24][25][26][27]29], comparable to our cohort (31%). We also recorded a considerable presence of fundus oculi abnormalities (15%), outlining the importance of ophthalmological examination. ...
... On the other hand, MRI abnormalities were described with high frequency in our cohort (60%), in particular slight increase of CNS liquoral spaces (20%). Microcephaly resulted more common in our series, if compared with literature [21][22][23][24][25][26][27]29]. ...
... g P7 and his mother. Long palpebral fissure, lower palpebral eversion, epicanthus and prominent ear in a patient of our cohort (on the left) and his affected mother (on the right) [20][21][22][23]. In our series, overweight or obesity was present only in adult patients and three adolescents, instead, presented generalized poor growth. ...
Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.
Conclusions : These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common
What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)
... This is consistent with previous reports of mean heights of over two standard deviations below average. Growth hormone deficiencies are present in a few cases [22]. KS children are generally born at term and with a normal birth weight. ...
Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.
... Growth and development in patients with pathogenic KDM6A variants Among patients with clinically diagnosed KS, 55-71% have short stature and 25-32% have microcephaly. [29][30][31] In our cohort of patients with pathogenic KDM6A variants short stature was less frequent (48%) and microcephaly was more frequent (54%) (Supplementary Table S1). Comparisons of SDs of weights, lengths/heights, and HCs at last examination against measurements at birth, clearly reveal that the growth retardation in this condition is mostly of postnatal origin. ...
... Congenital and sensory anomalies in patients with pathogenic KDM6A variants Cardiovascular anomalies were reported in 49.2% of patients of our cohort who underwent echocardiogram (Table 1 and Supplementary Table S1). This appears to be higher than the reported frequency of 37-42% in cases of KS. 29,30 The commonest congenital heart defect was atrial septal defect, followed by ventricular septal defect. Aortic anomalies such as coarctation, bicuspid valve, and stenosis were also frequent. ...
... The frequencies of palate and dental anomalies were high in our cohort (64.2% and 60%, respectively) ( Table 1 and Supplementary Table S1), but the presence of cleft lip/palate and hypodontia was lower (11.9% and 22.2%, respectively) when compared with previous reports (35-50% and 48-85%, respectively). [29][30][31]34 Around one third (31.3%) of patients in our cohort have strabismus, which has been reported in 21-36% of patients of with KS. 29,30,35 Interestingly, around 11% of patients in our cohort reported nystagmus. The basis of nystagmus in KS2 patients is unclear and needs further investigation. ...
Purpose
The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.
Methods
Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.
Results
Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID.
Conclusion
We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
... KS has been associated with an increased risk for development of feeding difficulties, autoimmune disorders, and immunodeficiency, and an increased susceptibility to respiratory infections [8][9][10][11][12]. Patients with KS also frequently present with a variety of skeletal and visceral anomalies including growth deficiency, cleft palate, renal and hepatic anomalies, anorectal malformations, and congenital heart defects (CHDs) [10,[13][14][15][16][17]. ...
... Among the most frequent additional symptoms are congenital heart defects and urogenital anomalies (Adam & Hudgins, 2005;Bögershausen & Wollnik, 2013;Digilio, Marino, Toscano, Giannotti, & Dallapiccola, 2001;Digilio et al., 2017;Hughes & Davies, 1994;Kawame, Hannibal, Hudgins, & Pagon, 1999;Lehman et al., 2017;Niikawa et al., 1988;Wessels, Brooks, Hoogeboom, Niermeijer, & Willems, 2002). Other findings that have been described in Kabuki syndrome patients include cleft palate, coloboma, microphthalmia, or atresia of the choanae (Badalato et al., 2017;Geneviève et al., 2004;Patel & Alkuraya, 2015;Sakata et al., 2017;Schulz, Freese et al., 2014;Verhagen, Oostdijk, van Terwisscha Scheltinga, Schalij-Delfos, & van Bever, 2014). ...
Neurocristopathies are human congenital syndromes that arise from defects in neural crest (NC) development and are typically associated with malformations of the craniofacial skeleton. Genetic analyses have been very successful in identifying pathogenic mutations, however, model organisms are required to characterize how these mutations affect embryonic development thereby leading to complex clinical conditions. The African clawed frog Xenopus laevis provides a broad range of in vivo and in vitro tools allowing for a detailed characterization of NC development. Due to the conserved nature of craniofacial morphogenesis in vertebrates, Xenopus is an efficient and versatile system to dissect the morphological and cellular phenotypes as well as the signaling events leading to NC defects. Here, we review a set of techniques and resources how Xenopus can be used as a disease model to investigate the pathogenesis of Kabuki syndrome and neurocristopathies in a wider sense.
... A previous expansive literature review found that strabismus was present in about 22% of 300 patients with a confirmed diagnosis of Kabuki syndrome [8]. However, these cases lack detailed documentation and only three cases reported the degrees of deviation most of which were found to be at small angles (12-25 PD). ...
Kabuki syndrome is an uncommon genetic disease associated with skeletal, cardiac, neurological, and ocular manifestations. Strabismus is an ophthalmic manifestation of Kabuki syndrome; however, it is infrequently documented in detail. We report a case of Kabuki syndrome in a patient who presented with large angle congenital esotropia. This case report highlights the importance of early eye examinations and subsequent interventions in patients diagnosed with Kabuki syndrome.
