RARE DISEASE
Kabuki syndrome
Kabuki syndrome
Kabuki syndrome
Synonyms: Kabuki make-up syndrome, Niikawa-Kuroki syndrome
Synonyms: Kabuki make-up syndrome, Niikawa-Kuroki syndrome
Synonyms: Kabuki make-up syndrome, Niikawa-Kuroki syndrome
Drug discovery
3
drugs
With orphan designations
Overview
Kabuki syndrome is a rare genetic disorder caused by pathogenic variants in KMT2D (75% of cases) or KDM6A (5%), characterized by distinctive facial features, developmental delay, intellectual disability, growth deficiencies, and multi-system involvement (cardiac, skeletal, immunological, and endocrine) [2][5][16]. Diagnosis relies on clinical evaluation and genetic testing, with management focusing on multidisciplinary symptomatic care [1][6][13].
Therapies
Multidisciplinary care: Coordinated input from genetics, endocrinology, cardiology, and rehabilitation therapies (physical, occupational, speech) [1][6][8][13].
Early intervention: Targeted therapies for hypotonia, developmental delays, and comorbidities (e.g., growth hormone for short stature, anticonvulsants for seizures) [3][6][8].
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare surgical thoracic diseases, rare transplant-related disorders
Research Papers
124 drug discovery papers about Kabuki syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
124 drug discovery papers about Kabuki syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2024-09-22 | The Effects of Growth Hormone Treatment Beyond Growth Promotion in Patients with Genetic Syndromes: A Systematic Review of the Literature
Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader–Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with rhGH as growth hormone-deficient individuals or as children born small for their gestational age. After years of experience with this therapy in syndromic short stature, it has been proved that there are some aspects of long-term rhGH treatment beyond growth promotion, which can justify rhGH use in these individuals. This paper summarizes the data of a literature review of the effects of rhGH treatment beyond growth promotion in selected genetic syndromes. We chose three of the most common syndromes, Prader–Willi, Turner, and Noonan, in which rhGH treatment is indicated, and three rarer syndromes, Silver–Russel, Kabuki, and Duchenne muscular dystrophy, in which rhGH treatment is not widely indicated. Many studies have shown a significant impact of rhGH therapy on body composition, resting energy expenditure, insulin sensitivity, muscle tonus, motor function, and mental and behavioral development. Growth promotion is undoubtedly the primary benefit of rhGH therapy; nevertheless, especially with genetic syndromes, the additional effects should also be considered as important indications for this treatment.
2022-03-31 | Follow-Up Study of Growth Hormone Therapy in Children with Kabuki Syndrome: Two-Year Treatment Results.
Kabuki syndrome (KS) is a genetic disorder with characteristic facial dysmorphisms, short stature, hypertension, and obesity later in life. The aim of this study was to evaluate catch-up growth and cardiovascular markers before and during growth hormone (rhGH) treatment in KS children. This prospective study included 18 children whose KS was genetically established. Each KS subject received rhGH for a period of 2 years. Several measurements were performed before and during treatment: anthropometry, glucose metabolism, lipid profile, markers for endothelial function, and low-grade inflammation. This study found an increase in delta height standard deviation score (SDS) for the whole group of 1.1 SDS after 2 years of rhGH treatment. Baseline metabolic profiles showed no cardiometabolic abnormalities in these children. Although 4 out of 18 children were obese, there were no signs of the metabolic syndrome. During rhGH treatment, serum low-density lipoprotein cholesterol concentrations decreased significantly (2.16-1.91 mmol/L, p = 0.04). Apolipoprotein B100 concentrations also showed a reduction after 24 months of treatment, but the other lipid and (apo)lipoprotein parameters did not change. While other endothelial function markers were stable, only vascular cell-adhesion molecule-1 concentrations increased (1,084-1,161 pg/mL, p < 0.01) during rhGH therapy. Furthermore, BMI and waist circumference improved during treatment. There were no signs of hypertension. At baseline and during rhGH therapy, there were no signs of the metabolic syndrome. This is the first study demonstrating that rhGH treatment in KS children is a safe and effective therapy and that it positively influences linear height without exerting adverse effects on a wide array of cardiovascular risk markers.
2019-11-25 | The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration
Abstract Kabuki syndrome is an autosomal dominant developmental disorder with high similarities to CHARGE syndrome. It is characterized by a typical facial gestalt in combination with short stature, intellectual disability, skeletal findings and additional features like cardiac and urogenital malformations, cleft palate, hearing loss and ophthalmological anomalies. The major cause of Kabuki syndrome are mutations in KMT2D, a gene encoding a histone H3 lysine 4 (H3K4) methyltransferase belonging to the group of chromatin modifiers. Here we provide evidence that Kabuki syndrome is a neurocrestopathy, by showing that Kmt2d loss-of-function inhibits specific steps of neural crest (NC) development. Using the Xenopus model system, we find that Kmt2d loss-of-function recapitulates major features of Kabuki syndrome including severe craniofacial malformations. A detailed marker analysis revealed defects in NC formation as well as migration. Transplantation experiments confirm that Kmt2d function is required in NC cells. Furthermore, analyzing in vivo and in vitro NC migration behavior demonstrates that Kmt2d is necessary for cell dispersion but not protrusion formation of migrating NC cells. Importantly, Kmt2d knockdown correlates with a decrease in H3K4 monomethylation and H3K27 acetylation supporting a role of Kmt2d in the transcriptional activation of target genes. Consistently, using a candidate approach, we find that Kmt2d loss-of-function inhibits Xenopus Sema3F expression, and overexpression of Sema3F can partially rescue Kmt2d loss-of-function defects. Taken together, our data reveal novel functions of Kmt2d in multiple steps of NC development and support the hypothesis that major features of Kabuki syndrome are caused by defects in NC development.
2018-12-17 | Hypermobility in individuals with Kabuki syndrome: The effect of growth hormone treatment
Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D ‐associated, autosomal‐dominant KS type 1 (KS1; OMIM 147920); and KDM6A ‐associated, X‐linked‐dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS.
2017-08-09 | Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results
Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children.In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured.This study showed an increase in height standard deviation score (SDS) for the whole group from -2.40 to -1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was -0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects' body proportions remained normal.All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.
small molecules
2026-08-13 | Chromatin condensates tune nuclear mechanosensing and preserve nuclear integrity to prevent cGAS activation.
Cells and tissue integrity are constantly challenged by the necessity to adapt and respond to mechanical loads. Among cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. Here we investigate whether the mechanical properties of chromatin and its organization into condensates contribute to nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we find that the balancing of transcriptional and Polycomb condensates tunes nuclear responsiveness to external mechanical forces. MLL4 assembles into mechanosensitive condensates through its prion-like domain, and this response is regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome, persistent nuclear envelope rupture triggers cGAS-STING activation, leading to programmed cell death. Together, these findings identify chromatin condensates as active regulators of nuclear mechanosensing and establish a mechanistic link between defective chromatin organization and cGAS-STING activation in Kabuki syndrome.
2026-03-24 | A Novel KMT2D Variant with Treatable Secondary Mitochondrial Myopathy in a Lebanese Female with Kabuki Syndrome
Kabuki syndrome (KS) is a multisystem disorder primarily caused by mutations in the KMT2D gene. We report here a 20-year-old female with a novel KMT2D variant (c.4690G>A) presenting with multiple autoimmune conditions (Type 1 Diabetes, Graves’ disease, Celiac disease) and a Type B2 Thymoma. Her presenting symptoms were a secondary mitochondrial myopathy with diabetes, with a proximal weakness and elevated lactate blood level. Neuromuscular function showed sustained recovery following mitochondrial support therapy with L-Carnitine and Coenzyme Q10. This case is the first reported novel KS variant in the Lebanese population, with a secondary mitochondrial myopathy responding to treatment.
2026-03-19 | Loss of KMT2D accelerates hypertrophic chondrocyte differentiation and senescence by increasing mitochondrial ROS production
Abstract Longitudinal bone growth occurs through endochondral ossification, which is accompanied by the differentiation of chondrocytes in the growth plate. Disruption in chondrocyte maturation can lead to skeletal growth abnormalities, such as those observed in Kabuki syndrome type 1 (KS1), a genetic disorder caused by heterozygous pathogenic variants in the KMT2D gene. KS1 patients exhibit postnatal growth deficiency, craniofacial hypoplasia, and skeletal deformities, yet the mechanisms underlying these phenotypic manifestations remain poorly understood. Our study investigated the effects of KMT2D deficiency on chondrocyte maturation and identified premature chondrocyte hypertrophy as a key driver of skeletal abnormalities in KS1. We previously observed reduced femur and tibia length in a KS1 mouse model, along with altered growth plate architecture, particularly affecting the heights of the proliferative and hypertrophic zones. Here, we show that KMT2D-deficient chondrocytes exhibit accelerated differentiation and early senescence upon exposure to supraphysiological oxygen levels (20% O 2 ). These pathological changes were linked to increased mitochondrial reactive oxygen species (ROS) production likely caused by deficiencies in electron transport chain function, leading to oxidative stress and premature hypertrophy. Pharmacological ROS neutralization or hypoxic conditions mitigated these effects, restoring normal chondrocyte differentiation and preventing premature ossification. These findings demonstrate that KMT2D loss induces oxidative stress-driven chondrocyte hypertrophy, disrupting the balance of cartilage growth and ossification. Our study provides crucial mechanistic insights into KS1-associated skeletal abnormalities and suggests mitochondrial ROS regulation as a potential therapeutic avenue.
2026-02-16 | Clinical Presentation and Molecular Characteristics of Kabuki Syndrome With Congenital Hyperinsulinism: A Retrospective Study.
Kabuki syndrome (KS) is a rare disease predisposing to congenital hyperinsulinism (CHI). The incidence of CHI in KS may be higher than considered in practice, and appropriate management of hypoglycemia would reduce long-term neurologic morbidity in these patients. Thus, the aims of our study were to estimate the occurrence rate of CHI-related hypoglycaemia in KS, to describe its evolution, and to identify potential genotype-phenotype correlations. We conducted a single-centre retrospective study in patients with KS from 1999 to 2024. Among the 18 patients identified with KS included in the study, six (33%) presented neonatal hypoglycaemia, of whom five (28%) demonstrated CHI. Of these five, three had persistent CHI. Only the three patients with this condition required anti-hypoglycaemic drugs. They all responded well to diazoxide monotherapy, and one then needed the addition of octreotide. Genetically, all patients had heterozygous variants of the KMT2D gene except one, who had a heterozygous microdeletion of the same gene. Among these 17 variants, the majority were truncating variants (10/17, 59%) (three nonsense variants, six frameshift variants, and one splicing variant). Seven variants were missense variants (7/17, 41%). Among the six patients with hypoglycaemia, all had nonsense or frameshift variants in the C-terminal part of the KMT2D protein. This study illustrates the importance of systematic screening for hypoglycaemia in patients with early diagnosis of KS. Conversely, newborns or infants with CHI should be considered and possibly tested for this etiological diagnosis.
2026-01-13 | Kabuki Syndrome Presenting with Congenital Hyperinsulinemic Hypoglycemia: The First Neonatal Case Reports in Korea
Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive craniofacial features, skeletal anomalies, dermatoglyphic variations, intellectual disability, and postnatal growth restriction.Pathogenic variants in KMT2D and KDM6A are identified in approximately 80% of affected individuals.Although hypoglycemia has been regarded as an uncommon manifestation, emerging evidence suggests that hyperinsulinemic hypoglycemia (HH) may represent an underrecognized feature of KS, particularly in neonates before characteristic dysmorphic features become apparent.We describe two neonates with genetically confirmed KS who initially presented with HH, representing the first reported cases of this association in Korea.A KDM6A mutation was identified in Patient 1, and diazoxide treatment successfully maintained normoglycemia.Patient 2 carried a KMT2D mutation and demonstrated improvement following treatment with diazoxide and hydrocortisone, allowing discontinuation of therapy.Persistent HH during the neonatal period may serve as an early indicator of KS, prompting timely genetic testing.
cell therapies
2026-04-11 | Epigenetic signature at FOXP3 distal enhancer affects regulatory T cell development in Kabuki syndrome
Abstract Kabuki syndrome (KS) is a congenital developmental disorder caused by germinal pathogenic variants in the lysine methyltransferase 2D (KMT2D, KS1) or lysine demethylase 6A (KDM6A, KS2) genes. Kabuki patients display mental retardation, multiorgan malformations and immune dysregulation – ranging from immunodeficiency to autoimmunity – which strongly compromises their life expectancy. We explored whether the complex immunological scenario of Kabuki syndrome 1 subjects (Ks) could be ascribed to an altered generation of CD4 + FOXP3 + regulatory T cells (Tregs). We report that pediatric Ks carrying KMT2D pathogenic variants show a significant reduction of Tregs. DNA methylation analysis reveals a specific methylation pattern at the FOXP3 distal enhancer that correlates with decreased FOXP3 transcription early during Treg cell induction and promotes T helper (Th)-2 lineage differentiation. Finally, in vitro T cell demethylation rescues FOXP3 expression and Treg induction in Ks, offering a novel potential therapeutic perspective. Our findings connect KMT2D loss-of-function to the inhibition of human FOXP3 gene transcription and provide novel molecular insights to explain the immunological phenotype in Ks, thus pinpointing this syndrome as a novel Tregopathy.
2026-01-16 | Proximal Junctional Kyphosis Following Spinal Thoracic Deformity Correction in a Patient with Kabuki Syndrome: A Case Report.
Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facial features, intellectual disability, and multiple musculoskeletal anomalies, including scoliosis, kyphosis, and generalized ligamentous laxity. The combination of connective tissue fragility and complex spinal deformity may predispose these patients to post-operative complications, such as proximal junctional kyphosis (PJK), though this association has not previously been reported. We report a 15-year-old male with genetically confirmed KS who presented with severe thoracic hyperkyphosis (95°). Posterior spinal fusion and correction were performed, resulting in initial improvement. Within 8 months, the patient developed PJK above the upper instrumented vertebra, requiring multiple revision procedures. Post-operative infection with Staphylococcus aureus and rapid recurrent kyphosis further complicated management. A staged revision strategy, combining halo-gravitational traction followed by extended fusion and careful sagittal realignment, achieved stable correction and functional improvement at 1-year follow-up. The association between these conditions has, to our knowledge, not yet been reported in literature. This case highlights the multifactorial etiology of PJK in KS, where intrinsic ligamentous laxity, immune dysfunction, and extensive deformity correction converge to increase mechanical vulnerability. Soft-tissue preservation at the upper instrumented level, careful sagittal contouring, and infection control are key preventive strategies. Due to inherent ligamentous laxity and connective tissue abnormalities, patients with KS could be predisposed to proximal junctional failure after spinal deformity correction. Pre-operative recognition of connective tissue and immunologic abnormalities, together with detailed surgical planning, is essential to minimize complications and optimize long-term outcomes.
2021-11-12 | Lysine methyltransferase 2D regulates muscle fiber size and muscle cell differentiation.
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
2021-06-25 | Bonebridge implantation for mixed hearing loss in a patient with Kabuki syndrome.
The high prevalence of middle ear disease with related hearing loss in Kabuki syndrome requires the diagnostic and treatment expertise of otologists. This case report describes outcomes and changes in the quality of life of a patient affected by Kabuki syndrome with a history of recalcitrant chronic otitis media and mixed hearing loss who had undergone several unsuccessful surgical procedures before solving his problems by means of subtotal petrosectomy and active middle ear implant.
gene therapies
2026-01-01 | Cardiac Management Modifiers in Children With Common Genetic Syndromes: A Systematic Review and Practical Framework for Pediatric Cardiology
This registration describes the protocol for a systematic review with structured narrative synthesis on cardiac management modifiers in children with common genetic syndromes. The review will synthesize published evidence on cardiac manifestations, cardiac-care entry pathways, physiology categories, initial workup, stabilization needs, surveillance timing, outcome-triggered interventions, and syndrome-specific modifiers relevant to pediatric cardiology. The review will include selected genetic syndromes with clinically important pediatric cardiac implications, including Down syndrome, 22q11.2 deletion syndrome, Turner syndrome, Noonan syndrome/RASopathies, Williams syndrome, Marfan syndrome, Loeys-Dietz syndrome, Duchenne muscular dystrophy, mucopolysaccharidoses, Holt-Oram syndrome, tuberous sclerosis complex, Ellis–van Creveld syndrome, Alagille syndrome, CHARGE syndrome, and Kabuki syndrome. Formal database searching, study screening, data extraction, and quality assessment have not started at the time of registration.
2025-11-22 | Analysis of the clinical features of neurocristopathy-related hearing loss and how these relate to outcomes after cochlear implantation.
The clinical features of neurocristopathy-related hearing loss, and the correlation between these features and patient improvements after cochlear implantation (CI) are unknown. This study enrolled 16 children with sensorineural hearing loss due to four types of neurocristopathies, Waardenburg syndrome (WS), Noonan syndrome (NS), Kabuki syndrome (KS), and CHARGE syndrome (CS), who underwent CI. Neurodevelopmental assessment was conducted using the Gesell Developmental Schedules, ear development was evaluated using temporal bone computed tomography, and the post-CI auditory nerve response was assessed via neural response telemetry. Auditory performance was evaluated using the categories of the auditory performance scale. Genetic features were examined using whole-exome sequencing. WS/NS Groups achieved excellent auditory-speech outcomes (CAP_3 year/SIR_3 year: WS 7.3/4.0 n = 3, NS 8.0/4.0 n = 1), using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR), with minimal impact from SOX10 (WS) or PTPN11 (NS) mutations on neurodevelopment. CS Group showed poor recovery (CAP_3 year/SIR_3 year: 3.3/1.8 n = 3) due to CHD7-related cochlear nerve dysplasia and central auditory deficits, Gesell_mean showed a significant positive correlation with CAP_1 year (ρ = 0.83 n = 6 p = 0.042), CAP_3 year was significantly correlated with both implantation CI_age_mon and Gesell_mean independently (ρ = 1.0, n = 3, p < 0.001). Non-CS Groups(WS/NS/KS)showed older CI_age_mon predicted higher 1-year SIR (ρ = 0.77 n = 10 p = 0.009), while structural abnormalities (abnormal_sum) trended toward worse 3-year SIR (ρ=-0.79 n = 5). The integration of genetic, ear structure, and neurodevelopmental assessments can assist in clinical decision making for CI.
2025-08-01 | Abstract Thu165: X-linked Demethylase KDM6A is Differentially Required in Male and Female Hearts
Background: Sex differences are prevalent across many human diseases, including both adult and congenital cardiovascular disease. Uncovering the mechanisms driving these sex differences is necessary to advance clinical approaches for both men and women with heart disease. KDM6A (formally UTX) is an X-chromosome-linked H3K27 demethylase that specifically removes histone H3 lysine K27 trimethylation, thereby priming transcriptional activation. Mutations in KDM6A cause Kabuki syndrome in humans, a rare congenital craniofacial disorder commonly associated with heart defects. Studies in mice have shown that Kdm6a is critical for embryonic stem cell differentiation into cardiomyocytes (CMs) and global homozygous deletion of Kdm6a leads to embryonic lethality in female, but not male, mice due to developmental heart defects. While there is substantial evidence that KDM6A plays a critical role in the heart, the sex-specific epigenetic function of KDM6A within the heart remains unknown. Methods: We have employed a CM-specific KDM6A conditional null mouse model ( Kdm6a cmKO) to determine the sex-specific requirement for KDM6A in male and female hearts. Results: We find that KDM6A loss in CMs during heart development has sex-specific effects on cardiac conduction in adult mice. We also report widespread gene dysregulation in distinct pathways in male and female adult Kdm6a cmKO CMs, including opposing effects on genes involved in contractility, ion transport, and calcium ion homeostasis. Finally, we find that postnatal KDM6A loss exclusively impacts cardiac conduction in female mice and results in distinct electrocardiogram signatures compared to female Kdm6a cmKO mice. Discussion: Ongoing work aims to identify the sex-specific genomic targets of KDM6A at key developmental and postnatal time points. Overall, this research will define a sex-specific role for KDM6A in the epigenetic regulation of gene expression within the heart and will provide further insight into the biological mechanisms underlying sex differences in human heart physiology and disease.
2025-03-24 | Case Report: Area of focus clinical presentation and KMT2D gene mutation at the c.15535C>T site in a case of Kabuki syndrome.
Kabuki syndrome (KS) is a rare autosomal dominant genetic disorder. The full understanding of KS remains elusive due to the heterogeneity of gene mutations, clinical phenotypes, and the associations and mechanisms linking genotypes to phenotypes. This study reports on a 16-year-old male patient diagnosed with type I Kabuki syndrome following the identification of a de novo mutation, c.15535C>T (p.Arg5179Cys), in the KMT2D gene. A 16-year-old male presented with bilateral breast enlargement persisting for over 1 month. Historically, the patient exhibited intellectual disability. Both parents are healthy with no similar family history. The patient's father had a history of heroin use for 8 years prior to the patient's birth. On examination, the patient had unclear speech and slow speech rate, with diminished reading comprehension and calculation abilities. Characteristic facial features of KS were noted. Breast development was observed (Tanner stage II on the right and III on the left), with pain upon deep palpation of the left nipple. Molecular genetic testing identified a heterozygous missense mutation, c.15535C>T (p.Arg5179Cys), in theKMT2Dgene, confirming the diagnosis of type I Kabuki syndrome. KS is characterized by distinctive facial features: arched eyebrows, eversion of the eyelids, long palpebral fissures, a short nasal septum, a flat nasal tip, auricular deformities, a small mandible, a high palatal arch, or cleft palate. The patient exhibited a heterozygous missense mutation in the coding region of the KMT2D gene, identified as a de novo mutation. Currently, KS management primarily involves symptomatic and rehabilitative therapies.
2024-06-02 | Clinical and molecular characteristics of Korean patients with Kabuki syndrome.
Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. This study enhances the understanding of the clinical and genetic characteristics of KS.
other
2025-04-25 | Immune and Genetic Insights into Kabuki Syndrome: A Case Series
Introduction Kabuki syndrome is a rare disorder primarily associated with mutations in the KMT2D (autosomal dominant) and KDM6A (X-linked) genes. While these mutations may be linked to immune dysregulation, including humoral immunodeficiencies resembling common variable immunodeficiency with recurrent infections and impaired B cell memory differentiation [1], these associations are not well established. This study aims to further characterize immune dysregulation, clinical manifestations, and genetic variability in Kabuki syndrome to address this gap. Method This case series involves patients diagnosed with Kabuki syndrome at the University of Miami, following Institutional Review Board approval (Study #20240903). Electronic medical records were reviewed to analyze demographics, history of infections, autoimmunity, and relevant laboratory data. Findings The study included seven patients (4 males and 3 females), aged 14 months to 26 years (mean: 11.7 years, median: 5 years). Hypogammaglobulinemia was observed in 6/7 patients (86%), with low IgG in 4/7 (57%), low IgA in 2/7 (29%), and low IgM in 3/7 (43%). Lymphopenia was identified in 3/7 patients (43%) for CD3, 3/7 (43%) for CD4, and in 2/7 (29%) for CD8. 1/7 patients (14%) showed significant B cell subset abnormalities. Pathogenic or likely pathogenic KMT2D mutations were detected in 6/7 patients (86%), while 2/7 (29%) had variants of uncertain significance (CEP250, SALL1, and SRCAP). A duplication at 2q22.1 was noted in 1/7 patients (14%) without a clear clinical phenotype. Recurrent infections occurred in 3/7 patients (43%), mainly involving upper respiratory infections, otitis media, and pneumonia. Autoimmunity was reported in 1/7 patients (14%) and lymphoproliferative disorders in 2/7 (29%). Intravenous immunoglobulin therapy was administered to 3/7 patients (43%) and 1/7 (14%) received prophylactic vaccines for low pneumococcal antibody titers. Discussion This study finds that patients with Kabuki syndrome exhibit significant immune dysregulation, including hypogammaglobulinemia, lymphopenia, and recurrent infections, which are linked to genetic variability such as pathogenic KMT2D mutations and variants of uncertain significance. These findings support the need for routine immune evaluations, genetic testing, and targeted therapies, including immunoglobulin replacement and additional vaccinations, to guide personalized management and improve patient outcomes.
2023-02-02 | Episignature analysis of moderate effects and mosaics
Abstract Background: DNA methylation classifiers (“episignatures”) help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. Results: We improved episignatures with respect to three categories. Applying (i) a minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated retraining of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series in KMT2B down to moderate effect variants associated with comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D -associated Kabuki syndrome. Conversely, episignature classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico mosaics that represented all the possible variation in degree of mosaicism, variant read sampling, and methylation analysis.
2019-12-06 | Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome
BackgroundKabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified.ObjectiveWe sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses).MethodsWe performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS.ResultsCompared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line.ConclusionsKmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency. Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS. Compared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.
2009-11-12 | Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome.
Kabuki syndrome (KS) is often associated with autoimmune abnormalities, such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, leukoplakia and thyroiditis, as well as congenital anomalies. We herein present a KS patient with refractory ITP who achieved durable and complete remission in response to a total of four once-monthly infusions of rituximab. KS patients are often more susceptible to infection, so splenectomy should be avoided. Therefore, rituximab therapy is an alternative option for KS patients with ITP who fail to respond to first-line therapy.
proteins
2024-09-22 | The Effects of Growth Hormone Treatment Beyond Growth Promotion in Patients with Genetic Syndromes: A Systematic Review of the Literature
Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader–Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with rhGH as growth hormone-deficient individuals or as children born small for their gestational age. After years of experience with this therapy in syndromic short stature, it has been proved that there are some aspects of long-term rhGH treatment beyond growth promotion, which can justify rhGH use in these individuals. This paper summarizes the data of a literature review of the effects of rhGH treatment beyond growth promotion in selected genetic syndromes. We chose three of the most common syndromes, Prader–Willi, Turner, and Noonan, in which rhGH treatment is indicated, and three rarer syndromes, Silver–Russel, Kabuki, and Duchenne muscular dystrophy, in which rhGH treatment is not widely indicated. Many studies have shown a significant impact of rhGH therapy on body composition, resting energy expenditure, insulin sensitivity, muscle tonus, motor function, and mental and behavioral development. Growth promotion is undoubtedly the primary benefit of rhGH therapy; nevertheless, especially with genetic syndromes, the additional effects should also be considered as important indications for this treatment.
2022-03-31 | Follow-Up Study of Growth Hormone Therapy in Children with Kabuki Syndrome: Two-Year Treatment Results.
Kabuki syndrome (KS) is a genetic disorder with characteristic facial dysmorphisms, short stature, hypertension, and obesity later in life. The aim of this study was to evaluate catch-up growth and cardiovascular markers before and during growth hormone (rhGH) treatment in KS children. This prospective study included 18 children whose KS was genetically established. Each KS subject received rhGH for a period of 2 years. Several measurements were performed before and during treatment: anthropometry, glucose metabolism, lipid profile, markers for endothelial function, and low-grade inflammation. This study found an increase in delta height standard deviation score (SDS) for the whole group of 1.1 SDS after 2 years of rhGH treatment. Baseline metabolic profiles showed no cardiometabolic abnormalities in these children. Although 4 out of 18 children were obese, there were no signs of the metabolic syndrome. During rhGH treatment, serum low-density lipoprotein cholesterol concentrations decreased significantly (2.16-1.91 mmol/L, p = 0.04). Apolipoprotein B100 concentrations also showed a reduction after 24 months of treatment, but the other lipid and (apo)lipoprotein parameters did not change. While other endothelial function markers were stable, only vascular cell-adhesion molecule-1 concentrations increased (1,084-1,161 pg/mL, p < 0.01) during rhGH therapy. Furthermore, BMI and waist circumference improved during treatment. There were no signs of hypertension. At baseline and during rhGH therapy, there were no signs of the metabolic syndrome. This is the first study demonstrating that rhGH treatment in KS children is a safe and effective therapy and that it positively influences linear height without exerting adverse effects on a wide array of cardiovascular risk markers.
2019-11-25 | The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration
Abstract Kabuki syndrome is an autosomal dominant developmental disorder with high similarities to CHARGE syndrome. It is characterized by a typical facial gestalt in combination with short stature, intellectual disability, skeletal findings and additional features like cardiac and urogenital malformations, cleft palate, hearing loss and ophthalmological anomalies. The major cause of Kabuki syndrome are mutations in KMT2D, a gene encoding a histone H3 lysine 4 (H3K4) methyltransferase belonging to the group of chromatin modifiers. Here we provide evidence that Kabuki syndrome is a neurocrestopathy, by showing that Kmt2d loss-of-function inhibits specific steps of neural crest (NC) development. Using the Xenopus model system, we find that Kmt2d loss-of-function recapitulates major features of Kabuki syndrome including severe craniofacial malformations. A detailed marker analysis revealed defects in NC formation as well as migration. Transplantation experiments confirm that Kmt2d function is required in NC cells. Furthermore, analyzing in vivo and in vitro NC migration behavior demonstrates that Kmt2d is necessary for cell dispersion but not protrusion formation of migrating NC cells. Importantly, Kmt2d knockdown correlates with a decrease in H3K4 monomethylation and H3K27 acetylation supporting a role of Kmt2d in the transcriptional activation of target genes. Consistently, using a candidate approach, we find that Kmt2d loss-of-function inhibits Xenopus Sema3F expression, and overexpression of Sema3F can partially rescue Kmt2d loss-of-function defects. Taken together, our data reveal novel functions of Kmt2d in multiple steps of NC development and support the hypothesis that major features of Kabuki syndrome are caused by defects in NC development.
2018-12-17 | Hypermobility in individuals with Kabuki syndrome: The effect of growth hormone treatment
Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D ‐associated, autosomal‐dominant KS type 1 (KS1; OMIM 147920); and KDM6A ‐associated, X‐linked‐dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS.
2017-08-09 | Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results
Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children.In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured.This study showed an increase in height standard deviation score (SDS) for the whole group from -2.40 to -1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was -0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects' body proportions remained normal.All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.
small molecules
2026-08-13 | Chromatin condensates tune nuclear mechanosensing and preserve nuclear integrity to prevent cGAS activation.
Cells and tissue integrity are constantly challenged by the necessity to adapt and respond to mechanical loads. Among cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. Here we investigate whether the mechanical properties of chromatin and its organization into condensates contribute to nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we find that the balancing of transcriptional and Polycomb condensates tunes nuclear responsiveness to external mechanical forces. MLL4 assembles into mechanosensitive condensates through its prion-like domain, and this response is regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome, persistent nuclear envelope rupture triggers cGAS-STING activation, leading to programmed cell death. Together, these findings identify chromatin condensates as active regulators of nuclear mechanosensing and establish a mechanistic link between defective chromatin organization and cGAS-STING activation in Kabuki syndrome.
2026-03-24 | A Novel KMT2D Variant with Treatable Secondary Mitochondrial Myopathy in a Lebanese Female with Kabuki Syndrome
Kabuki syndrome (KS) is a multisystem disorder primarily caused by mutations in the KMT2D gene. We report here a 20-year-old female with a novel KMT2D variant (c.4690G>A) presenting with multiple autoimmune conditions (Type 1 Diabetes, Graves’ disease, Celiac disease) and a Type B2 Thymoma. Her presenting symptoms were a secondary mitochondrial myopathy with diabetes, with a proximal weakness and elevated lactate blood level. Neuromuscular function showed sustained recovery following mitochondrial support therapy with L-Carnitine and Coenzyme Q10. This case is the first reported novel KS variant in the Lebanese population, with a secondary mitochondrial myopathy responding to treatment.
2026-03-19 | Loss of KMT2D accelerates hypertrophic chondrocyte differentiation and senescence by increasing mitochondrial ROS production
Abstract Longitudinal bone growth occurs through endochondral ossification, which is accompanied by the differentiation of chondrocytes in the growth plate. Disruption in chondrocyte maturation can lead to skeletal growth abnormalities, such as those observed in Kabuki syndrome type 1 (KS1), a genetic disorder caused by heterozygous pathogenic variants in the KMT2D gene. KS1 patients exhibit postnatal growth deficiency, craniofacial hypoplasia, and skeletal deformities, yet the mechanisms underlying these phenotypic manifestations remain poorly understood. Our study investigated the effects of KMT2D deficiency on chondrocyte maturation and identified premature chondrocyte hypertrophy as a key driver of skeletal abnormalities in KS1. We previously observed reduced femur and tibia length in a KS1 mouse model, along with altered growth plate architecture, particularly affecting the heights of the proliferative and hypertrophic zones. Here, we show that KMT2D-deficient chondrocytes exhibit accelerated differentiation and early senescence upon exposure to supraphysiological oxygen levels (20% O 2 ). These pathological changes were linked to increased mitochondrial reactive oxygen species (ROS) production likely caused by deficiencies in electron transport chain function, leading to oxidative stress and premature hypertrophy. Pharmacological ROS neutralization or hypoxic conditions mitigated these effects, restoring normal chondrocyte differentiation and preventing premature ossification. These findings demonstrate that KMT2D loss induces oxidative stress-driven chondrocyte hypertrophy, disrupting the balance of cartilage growth and ossification. Our study provides crucial mechanistic insights into KS1-associated skeletal abnormalities and suggests mitochondrial ROS regulation as a potential therapeutic avenue.
2026-02-16 | Clinical Presentation and Molecular Characteristics of Kabuki Syndrome With Congenital Hyperinsulinism: A Retrospective Study.
Kabuki syndrome (KS) is a rare disease predisposing to congenital hyperinsulinism (CHI). The incidence of CHI in KS may be higher than considered in practice, and appropriate management of hypoglycemia would reduce long-term neurologic morbidity in these patients. Thus, the aims of our study were to estimate the occurrence rate of CHI-related hypoglycaemia in KS, to describe its evolution, and to identify potential genotype-phenotype correlations. We conducted a single-centre retrospective study in patients with KS from 1999 to 2024. Among the 18 patients identified with KS included in the study, six (33%) presented neonatal hypoglycaemia, of whom five (28%) demonstrated CHI. Of these five, three had persistent CHI. Only the three patients with this condition required anti-hypoglycaemic drugs. They all responded well to diazoxide monotherapy, and one then needed the addition of octreotide. Genetically, all patients had heterozygous variants of the KMT2D gene except one, who had a heterozygous microdeletion of the same gene. Among these 17 variants, the majority were truncating variants (10/17, 59%) (three nonsense variants, six frameshift variants, and one splicing variant). Seven variants were missense variants (7/17, 41%). Among the six patients with hypoglycaemia, all had nonsense or frameshift variants in the C-terminal part of the KMT2D protein. This study illustrates the importance of systematic screening for hypoglycaemia in patients with early diagnosis of KS. Conversely, newborns or infants with CHI should be considered and possibly tested for this etiological diagnosis.
2026-01-13 | Kabuki Syndrome Presenting with Congenital Hyperinsulinemic Hypoglycemia: The First Neonatal Case Reports in Korea
Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive craniofacial features, skeletal anomalies, dermatoglyphic variations, intellectual disability, and postnatal growth restriction.Pathogenic variants in KMT2D and KDM6A are identified in approximately 80% of affected individuals.Although hypoglycemia has been regarded as an uncommon manifestation, emerging evidence suggests that hyperinsulinemic hypoglycemia (HH) may represent an underrecognized feature of KS, particularly in neonates before characteristic dysmorphic features become apparent.We describe two neonates with genetically confirmed KS who initially presented with HH, representing the first reported cases of this association in Korea.A KDM6A mutation was identified in Patient 1, and diazoxide treatment successfully maintained normoglycemia.Patient 2 carried a KMT2D mutation and demonstrated improvement following treatment with diazoxide and hydrocortisone, allowing discontinuation of therapy.Persistent HH during the neonatal period may serve as an early indicator of KS, prompting timely genetic testing.
cell therapies
2026-04-11 | Epigenetic signature at FOXP3 distal enhancer affects regulatory T cell development in Kabuki syndrome
Abstract Kabuki syndrome (KS) is a congenital developmental disorder caused by germinal pathogenic variants in the lysine methyltransferase 2D (KMT2D, KS1) or lysine demethylase 6A (KDM6A, KS2) genes. Kabuki patients display mental retardation, multiorgan malformations and immune dysregulation – ranging from immunodeficiency to autoimmunity – which strongly compromises their life expectancy. We explored whether the complex immunological scenario of Kabuki syndrome 1 subjects (Ks) could be ascribed to an altered generation of CD4 + FOXP3 + regulatory T cells (Tregs). We report that pediatric Ks carrying KMT2D pathogenic variants show a significant reduction of Tregs. DNA methylation analysis reveals a specific methylation pattern at the FOXP3 distal enhancer that correlates with decreased FOXP3 transcription early during Treg cell induction and promotes T helper (Th)-2 lineage differentiation. Finally, in vitro T cell demethylation rescues FOXP3 expression and Treg induction in Ks, offering a novel potential therapeutic perspective. Our findings connect KMT2D loss-of-function to the inhibition of human FOXP3 gene transcription and provide novel molecular insights to explain the immunological phenotype in Ks, thus pinpointing this syndrome as a novel Tregopathy.
2026-01-16 | Proximal Junctional Kyphosis Following Spinal Thoracic Deformity Correction in a Patient with Kabuki Syndrome: A Case Report.
Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facial features, intellectual disability, and multiple musculoskeletal anomalies, including scoliosis, kyphosis, and generalized ligamentous laxity. The combination of connective tissue fragility and complex spinal deformity may predispose these patients to post-operative complications, such as proximal junctional kyphosis (PJK), though this association has not previously been reported. We report a 15-year-old male with genetically confirmed KS who presented with severe thoracic hyperkyphosis (95°). Posterior spinal fusion and correction were performed, resulting in initial improvement. Within 8 months, the patient developed PJK above the upper instrumented vertebra, requiring multiple revision procedures. Post-operative infection with Staphylococcus aureus and rapid recurrent kyphosis further complicated management. A staged revision strategy, combining halo-gravitational traction followed by extended fusion and careful sagittal realignment, achieved stable correction and functional improvement at 1-year follow-up. The association between these conditions has, to our knowledge, not yet been reported in literature. This case highlights the multifactorial etiology of PJK in KS, where intrinsic ligamentous laxity, immune dysfunction, and extensive deformity correction converge to increase mechanical vulnerability. Soft-tissue preservation at the upper instrumented level, careful sagittal contouring, and infection control are key preventive strategies. Due to inherent ligamentous laxity and connective tissue abnormalities, patients with KS could be predisposed to proximal junctional failure after spinal deformity correction. Pre-operative recognition of connective tissue and immunologic abnormalities, together with detailed surgical planning, is essential to minimize complications and optimize long-term outcomes.
2021-11-12 | Lysine methyltransferase 2D regulates muscle fiber size and muscle cell differentiation.
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
2021-06-25 | Bonebridge implantation for mixed hearing loss in a patient with Kabuki syndrome.
The high prevalence of middle ear disease with related hearing loss in Kabuki syndrome requires the diagnostic and treatment expertise of otologists. This case report describes outcomes and changes in the quality of life of a patient affected by Kabuki syndrome with a history of recalcitrant chronic otitis media and mixed hearing loss who had undergone several unsuccessful surgical procedures before solving his problems by means of subtotal petrosectomy and active middle ear implant.
gene therapies
2026-01-01 | Cardiac Management Modifiers in Children With Common Genetic Syndromes: A Systematic Review and Practical Framework for Pediatric Cardiology
This registration describes the protocol for a systematic review with structured narrative synthesis on cardiac management modifiers in children with common genetic syndromes. The review will synthesize published evidence on cardiac manifestations, cardiac-care entry pathways, physiology categories, initial workup, stabilization needs, surveillance timing, outcome-triggered interventions, and syndrome-specific modifiers relevant to pediatric cardiology. The review will include selected genetic syndromes with clinically important pediatric cardiac implications, including Down syndrome, 22q11.2 deletion syndrome, Turner syndrome, Noonan syndrome/RASopathies, Williams syndrome, Marfan syndrome, Loeys-Dietz syndrome, Duchenne muscular dystrophy, mucopolysaccharidoses, Holt-Oram syndrome, tuberous sclerosis complex, Ellis–van Creveld syndrome, Alagille syndrome, CHARGE syndrome, and Kabuki syndrome. Formal database searching, study screening, data extraction, and quality assessment have not started at the time of registration.
2025-11-22 | Analysis of the clinical features of neurocristopathy-related hearing loss and how these relate to outcomes after cochlear implantation.
The clinical features of neurocristopathy-related hearing loss, and the correlation between these features and patient improvements after cochlear implantation (CI) are unknown. This study enrolled 16 children with sensorineural hearing loss due to four types of neurocristopathies, Waardenburg syndrome (WS), Noonan syndrome (NS), Kabuki syndrome (KS), and CHARGE syndrome (CS), who underwent CI. Neurodevelopmental assessment was conducted using the Gesell Developmental Schedules, ear development was evaluated using temporal bone computed tomography, and the post-CI auditory nerve response was assessed via neural response telemetry. Auditory performance was evaluated using the categories of the auditory performance scale. Genetic features were examined using whole-exome sequencing. WS/NS Groups achieved excellent auditory-speech outcomes (CAP_3 year/SIR_3 year: WS 7.3/4.0 n = 3, NS 8.0/4.0 n = 1), using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR), with minimal impact from SOX10 (WS) or PTPN11 (NS) mutations on neurodevelopment. CS Group showed poor recovery (CAP_3 year/SIR_3 year: 3.3/1.8 n = 3) due to CHD7-related cochlear nerve dysplasia and central auditory deficits, Gesell_mean showed a significant positive correlation with CAP_1 year (ρ = 0.83 n = 6 p = 0.042), CAP_3 year was significantly correlated with both implantation CI_age_mon and Gesell_mean independently (ρ = 1.0, n = 3, p < 0.001). Non-CS Groups(WS/NS/KS)showed older CI_age_mon predicted higher 1-year SIR (ρ = 0.77 n = 10 p = 0.009), while structural abnormalities (abnormal_sum) trended toward worse 3-year SIR (ρ=-0.79 n = 5). The integration of genetic, ear structure, and neurodevelopmental assessments can assist in clinical decision making for CI.
2025-08-01 | Abstract Thu165: X-linked Demethylase KDM6A is Differentially Required in Male and Female Hearts
Background: Sex differences are prevalent across many human diseases, including both adult and congenital cardiovascular disease. Uncovering the mechanisms driving these sex differences is necessary to advance clinical approaches for both men and women with heart disease. KDM6A (formally UTX) is an X-chromosome-linked H3K27 demethylase that specifically removes histone H3 lysine K27 trimethylation, thereby priming transcriptional activation. Mutations in KDM6A cause Kabuki syndrome in humans, a rare congenital craniofacial disorder commonly associated with heart defects. Studies in mice have shown that Kdm6a is critical for embryonic stem cell differentiation into cardiomyocytes (CMs) and global homozygous deletion of Kdm6a leads to embryonic lethality in female, but not male, mice due to developmental heart defects. While there is substantial evidence that KDM6A plays a critical role in the heart, the sex-specific epigenetic function of KDM6A within the heart remains unknown. Methods: We have employed a CM-specific KDM6A conditional null mouse model ( Kdm6a cmKO) to determine the sex-specific requirement for KDM6A in male and female hearts. Results: We find that KDM6A loss in CMs during heart development has sex-specific effects on cardiac conduction in adult mice. We also report widespread gene dysregulation in distinct pathways in male and female adult Kdm6a cmKO CMs, including opposing effects on genes involved in contractility, ion transport, and calcium ion homeostasis. Finally, we find that postnatal KDM6A loss exclusively impacts cardiac conduction in female mice and results in distinct electrocardiogram signatures compared to female Kdm6a cmKO mice. Discussion: Ongoing work aims to identify the sex-specific genomic targets of KDM6A at key developmental and postnatal time points. Overall, this research will define a sex-specific role for KDM6A in the epigenetic regulation of gene expression within the heart and will provide further insight into the biological mechanisms underlying sex differences in human heart physiology and disease.
2025-03-24 | Case Report: Area of focus clinical presentation and KMT2D gene mutation at the c.15535C>T site in a case of Kabuki syndrome.
Kabuki syndrome (KS) is a rare autosomal dominant genetic disorder. The full understanding of KS remains elusive due to the heterogeneity of gene mutations, clinical phenotypes, and the associations and mechanisms linking genotypes to phenotypes. This study reports on a 16-year-old male patient diagnosed with type I Kabuki syndrome following the identification of a de novo mutation, c.15535C>T (p.Arg5179Cys), in the KMT2D gene. A 16-year-old male presented with bilateral breast enlargement persisting for over 1 month. Historically, the patient exhibited intellectual disability. Both parents are healthy with no similar family history. The patient's father had a history of heroin use for 8 years prior to the patient's birth. On examination, the patient had unclear speech and slow speech rate, with diminished reading comprehension and calculation abilities. Characteristic facial features of KS were noted. Breast development was observed (Tanner stage II on the right and III on the left), with pain upon deep palpation of the left nipple. Molecular genetic testing identified a heterozygous missense mutation, c.15535C>T (p.Arg5179Cys), in theKMT2Dgene, confirming the diagnosis of type I Kabuki syndrome. KS is characterized by distinctive facial features: arched eyebrows, eversion of the eyelids, long palpebral fissures, a short nasal septum, a flat nasal tip, auricular deformities, a small mandible, a high palatal arch, or cleft palate. The patient exhibited a heterozygous missense mutation in the coding region of the KMT2D gene, identified as a de novo mutation. Currently, KS management primarily involves symptomatic and rehabilitative therapies.
2024-06-02 | Clinical and molecular characteristics of Korean patients with Kabuki syndrome.
Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. This study enhances the understanding of the clinical and genetic characteristics of KS.
other
2025-04-25 | Immune and Genetic Insights into Kabuki Syndrome: A Case Series
Introduction Kabuki syndrome is a rare disorder primarily associated with mutations in the KMT2D (autosomal dominant) and KDM6A (X-linked) genes. While these mutations may be linked to immune dysregulation, including humoral immunodeficiencies resembling common variable immunodeficiency with recurrent infections and impaired B cell memory differentiation [1], these associations are not well established. This study aims to further characterize immune dysregulation, clinical manifestations, and genetic variability in Kabuki syndrome to address this gap. Method This case series involves patients diagnosed with Kabuki syndrome at the University of Miami, following Institutional Review Board approval (Study #20240903). Electronic medical records were reviewed to analyze demographics, history of infections, autoimmunity, and relevant laboratory data. Findings The study included seven patients (4 males and 3 females), aged 14 months to 26 years (mean: 11.7 years, median: 5 years). Hypogammaglobulinemia was observed in 6/7 patients (86%), with low IgG in 4/7 (57%), low IgA in 2/7 (29%), and low IgM in 3/7 (43%). Lymphopenia was identified in 3/7 patients (43%) for CD3, 3/7 (43%) for CD4, and in 2/7 (29%) for CD8. 1/7 patients (14%) showed significant B cell subset abnormalities. Pathogenic or likely pathogenic KMT2D mutations were detected in 6/7 patients (86%), while 2/7 (29%) had variants of uncertain significance (CEP250, SALL1, and SRCAP). A duplication at 2q22.1 was noted in 1/7 patients (14%) without a clear clinical phenotype. Recurrent infections occurred in 3/7 patients (43%), mainly involving upper respiratory infections, otitis media, and pneumonia. Autoimmunity was reported in 1/7 patients (14%) and lymphoproliferative disorders in 2/7 (29%). Intravenous immunoglobulin therapy was administered to 3/7 patients (43%) and 1/7 (14%) received prophylactic vaccines for low pneumococcal antibody titers. Discussion This study finds that patients with Kabuki syndrome exhibit significant immune dysregulation, including hypogammaglobulinemia, lymphopenia, and recurrent infections, which are linked to genetic variability such as pathogenic KMT2D mutations and variants of uncertain significance. These findings support the need for routine immune evaluations, genetic testing, and targeted therapies, including immunoglobulin replacement and additional vaccinations, to guide personalized management and improve patient outcomes.
2023-02-02 | Episignature analysis of moderate effects and mosaics
Abstract Background: DNA methylation classifiers (“episignatures”) help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. Results: We improved episignatures with respect to three categories. Applying (i) a minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated retraining of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series in KMT2B down to moderate effect variants associated with comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D -associated Kabuki syndrome. Conversely, episignature classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico mosaics that represented all the possible variation in degree of mosaicism, variant read sampling, and methylation analysis.
2019-12-06 | Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome
BackgroundKabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified.ObjectiveWe sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses).MethodsWe performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS.ResultsCompared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line.ConclusionsKmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency. Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS. Compared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.
2009-11-12 | Successful treatment with rituximab of refractory idiopathic thrombocytopenic purpura in a patient with Kabuki syndrome.
Kabuki syndrome (KS) is often associated with autoimmune abnormalities, such as idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, leukoplakia and thyroiditis, as well as congenital anomalies. We herein present a KS patient with refractory ITP who achieved durable and complete remission in response to a total of four once-monthly infusions of rituximab. KS patients are often more susceptible to infection, so splenectomy should be avoided. Therefore, rituximab therapy is an alternative option for KS patients with ITP who fail to respond to first-line therapy.
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Drug Discovery Landscape
3 orphan drug designations for Kabuki syndrome.
3 orphan drug designations for Kabuki syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dabrafenib | small molecules | FDA | 2020-10-19 | — | Rescindo Therapeutics Inc. |
5-{(1R,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl}-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide monohydrochloride | small molecules | EMA | 2018-11-20 | — | Takeda Pharma A/S |
5-{(1R,2R)-2-[(Cyclopropylmethyl)amino]cyclopropyl}-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide monohydrochloride | small molecules | FDA | 2018-04-26 | — | Takeda Development Center Americas, Inc. |
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