Kabuki syndrome is a rare monogenic disease characterized by peculiar phenotypic features and intellectual deficiency. Patients have facial features (almond-shaped incision of the eyes, strabismus, arched eyebrows, wide bridge of the nose, low-set protruding ears, etc.), skeletal anomalies, defects of internal organs, oligophrenia. Diagnosis is based on clinical criteria confirmed by genetic analyses. Treatment is reduced to correction of congenital anomalies that threaten the life and health of the child, therapy of concomitant disorders (autoimmune, endocrine, infectious, etc.).
ICD 10
Q87.0 Q87.5
General information
Kabuki mask syndrome (Kabuki makeup syndrome) got its name from the appearance and facial expression of patients, giving them a resemblance to the characters of the Japanese theater of the same name. It is known that Kabuki Theater actors put special makeup on their faces, highlighting their eyes and eyebrows, and at the climactic moments of the performance they freeze in place, staring at one point and reducing their eyes to the bridge of their nose. The pathology was described in 1981 by two authors who presented observations of patients with characteristic phenotypic features, and in their honor is also called Niikawa-Kuroki syndrome. The syndrome belongs to the orphan category: in Japan its frequency is 1:32000, in the West – 1:86000. To date, about 350 cases of the disease have been described.
Causes
Pathology has a heterogeneous etiology. It is known that the syndrome is congenital. Most of the diagnosed cases of the disease are sporadic and develop due to mutations that occur “de novo”. The factors influencing the variability have not been determined. In 2010-2012, the two most frequently registered hereditary forms of the syndrome were studied, which are based on gene mutations:
- KMT2D (MLL2). The gene encodes lysine-specific methyltransferase 2D, located at the 12q13.12 locus. The mutation causes the first type of disease (KS1) with autosomal dominant inheritance. It is found in 70% of patients.
- KDM6A. The gene is located at the Xp11.3 site, encodes lysine-specific 6A demethylase, acts as a KMT2 cofactor. The gene defect is associated with the development of the second type of syndrome (KS2), which has an inheritance linked to the X chromosome. It accounts for about 5% of cases of pathology.
In genetic studies, there are data on the combination of Kabuki syndrome with other hereditary diseases: Fraser syndrome, hypokalemic periodic paralysis, Fanconi syndrome, type 1 diabetes mellitus. It is reported that patients have structural rearrangements of chromosomes, such as the ring X chromosome, translocations, duplications, inversions of chromosome 8. A relatively small sample of patients and the relatively recent introduction of molecular cytogenetic diagnostic methods leave prospects for further studies of the etiology of the syndrome.
Pathogenesis
Due to the incomplete study of the causes of Niikawa-Kuroki syndrome, the pathological mechanisms also remain insufficiently clear. The role and influence of mutations in the KMT2D and KDM6A genes are most highlighted. Both genes act as epigenetic regulators of histone modification (nuclear proteins) and play an important role in the process of gene expression. Defects of the enzymes encoded by them alter the methylation of lysine in histone H3, which leads to the development of heterogeneous congenital anomalies (craniofacial, skeletal, visceral), neurological and endocrine disorders. In addition, KMT2D and KDM6A are involved in the differentiation of naive CD4+ T lymphocytes into immunocompetent cells. This explains the fact that many patients with Kabuki syndrome have immune disorders, manifested both by a decrease in anti-infective protection and autoimmune disorders.
Symptoms
The clinical picture is characterized by multiple defects affecting various anatomical systems: the facial skeleton, musculoskeletal system, skin, cardiovascular system, gastrointestinal tract, genitourinary organs, analyzers, etc. Neurological, endocrine, and immune status disorders of varying severity are also detected. The most pathognomonic for the syndrome are facial dysmorphic disorder, which makes patients’ faces look like a mask of kabuki theater actors, stunting and decreased intelligence.
Facial anomalies include microcephaly, highly raised (arched) eyebrows, hypertelorism, antimongoloid ocular slit (omission of the outer corners of the eyes relative to the inner ones), ectropion of the lower eyelid. The portrait of a patient with Kabuki syndrome is complemented by low-lying protruding and deformed ears, a wide flattened nose, a small mouth with thin lips. Less often there is a bluish coloration of the sclera, palatine cleft, cleft lip, micrognathia, dental anomalies (hypodontia, microdontia, malocclusion). A peculiar facial expression is noticeable already in early childhood, but over the years the features acquire an even more rude and grotesque appearance.
Deviations in the development of the osteoarticular system are represented by deformity of the vertebrae, scoliosis, underdevelopment of tubular bones, polymorphic anomalies of the fingers (brachydactyly, syndactyly, arachnodactyly, clinodactyly), deformity of the foot. Already in the first year of life, growth retardation is detected, in the subsequent stunting persists and becomes more noticeable. Hypermobility of the joints is characteristic, which is the cause of frequent dislocations. On the part of the skin, there is hyperelasticity of the skin, the presence of hypo- and hyperpigmented spots, hyperemia of the facial skin, alopecia and hirsutism. An important dermatoglyphic marker is the protruding pads of the fingers.
Of the visceral defects in Kabuki syndrome, the most frequent and clinically significant are CHD (septum defects, single ventricle, aortic coarctation, tetrad of Fallot, transposition of the main vessels), gastrointestinal anomalies (incomplete bowel rotation, atresia of the anus, congenital diaphragmatic hernias), malformations of the urinary tract (hydronephrosis, horseshoe kidney). Girls may have premature telarche, boys – cryptorchidism, hydrocele and micropenis.
Anatomical defects are accompanied by functional disorders ‒ malabsorption and cholestasis syndromes, cardiac blockages, ureteral reflux. Pathology of the visual analyzer includes myopia, astigmatism, cataract, ptosis, strabismus. Most children are diagnosed with hearing loss.
Neurological disorders are found in 80% of patients: muscle hypotension, tremor, convulsions, epilepsy, ZPRR. The degree of oligophrenia varies from mild to moderate. There may be features of autistic behavior, obsessive-compulsive syndrome.
Due to defects in immune regulation and a decrease in serum Ig levels, frequent infections, autoimmune pathologies (thrombocytopenic purpura, hemorrhagic vasculitis.), hematological diseases (hemolytic anemia) are noted. Of hormonal disorders, type 1 diabetes, congenital hypothyroidism, decreased secretion of STH and ACTH, and obesity are the most frequent.
Complications
Potential complications are closely related to those multisystem lesions that the child has. In newborns, serious violations of sucking and swallowing are possible, requiring the installation of a gastric probe or gastrostomy. Also in infancy, unexplained episodes of hypoglycemia are noted, threatening to transition into a hypoglycemic coma. Congenital heart defects can cause serious hemodynamic disorders that require cardiac surgery. Frequent acute respiratory infections are often complicated by otitis media, pneumonia. Progressive atrophy of the optic nerves can lead to blindness. Patients with Kabuki syndrome have an increased risk of developing lymphocytic leukemia and non-Hodgkin’s lymphomas.
Diagnostics
The main problem of diagnosis is the low awareness of primary care specialists about this syndrome, the lack of clearly developed clinical criteria and methods of laboratory verification of the disease. Diagnosis is mainly based on phenotypic markers; genetic testing is available in large medical centers. The primary diagnosis is carried out by a geneticist, but patients with Kabuki syndrome require examination and supervision by a number of specialists: pediatrician, cardiologist, neurologist, orthopedist, urologist, immunologist, orthodontist, etc. The stages of the survey include:
- Portrait diagnostics. The core of the signs are facial stigmas, stunting, skeletal anomalies. In addition to high-frequency manifestations, rare atypical signs known from the descriptions of individual clinical observations (vitiligo, multiple hemangiomas, hypospadias) are also taken into account.
- Genetic research. Performed in specialized laboratory centers. They allow us to study the mutational status of the MLL2 and KDM6A genes. Methods of fluorescence (FISH) and comparative genomic hybridization on microchips (aCGH) are used for high-precision diagnostics. Parents must be examined for the presence of similar mutations.
- Laboratory diagnostics. The hemogram is characterized by thrombocytopenia, leukopenia, neutropenia. Hormonal and immunological tests are performed to detect concomitant disorders. The glycemic profile, the level of thyroid and pituitary hormones, immunoglobulins, and CEC are examined.
- Instrumental examination. It is carried out in order to identify concomitant organ disorders. Primary diagnostics includes EchoCG, ultrasound of the abdominal cavity and kidneys, radiography of bones and spine. Video EEG monitoring is performed during episindrome. Additionally, an ophthalmological examination and audiometry are performed.
At high risks of having a child with genetic abnormalities, invasive prenatal diagnosis is prescribed, followed by genome-wide sequencing. Differential diagnosis is carried out with other genetic syndromes accompanied by multiple developmental disorders: DiGeorge, Van der Woude, Melnik-Fraser, Ehlers-Danlo, Charge and others.
Treatment
Due to the genetic determinism of the disease, a complete cure is impossible. The standards of therapy for the syndrome are not regulated, in practice, a symptomatic approach is used to eliminate those disorders that interfere with the development of the child. Surgical pathology (hernias, CHD, cleft CHLO, anal atresia, cryptorchidism, etc.) are eliminated during surgical treatment.
Concomitant autoimmune disorders are corrected by the appointment of glucocorticoids, immunosuppressants, monoclonal antibodies. Recurrent infectious processes dictate the need for the use of antibacterial agents, intravenous administration of human immunoglobulin. When type 1 diabetes is detected, the issue of prescribing insulin therapy is resolved.
Prognosis and prevention
Children suffering from Kabuki syndrome need constant care and supervision, social adaptation, inclusive education. A family raising such a child needs psychological support. Due to the large number of complex defects (anatomical, immunological, endocrine, neurological), the quality and life expectancy of patients are reduced. Prevention of sporadic cases of the syndrome has not been developed, the leading role here is given to competent pre-gravidar preparation, exclusion of exposure to mutagenic environmental factors. Genetic counseling allows to find out the probability of inheritance of Kabuki syndrome by a child in the presence of family cases of pathology.