Kabuki syndrome

¿Que es Kabuki syndrome?

Kabuki syndromees un trastorno genético poco común y ocurre solo en 1 de 32,000 nacimientos. La condición afecta a hombres y mujeres por igual.

Se caracteriza por rasgos faciales específicos, que incluyen cejas arqueadas y ojos muy abiertos.

Condiciones de salud asociadas con Kabuki syndrome puede incluir baja estatura, anomalías inmunológicas y ojos alargados, similares a los pintados en los actores de teatro Kabuki japoneses, de ahí el nombre. En términos médicos, esta forma de ojo se denomina fisuras palpebrales con eversión del tercio lateral del párpado inferior. Hasta la mitad de los pacientes pueden presentar defectos cardíacos congénitos. La discapacidad intelectual media-moderada y el retraso del desarrollo también son una característica del síndrome.

Síndrome Sinónimos:
Maquillaje Kabuki síndrome, Kabuki syndrome, 1 KMS, Niikawa-Kuroki síndrome

¿Qué causan los cambios genéticos Kabuki syndrome?

Kabuki syndromees una condición genética causada por mutaciones en los genes KMT2D y KDM6A. Investigaciones recientes sugieren que las mutaciones en otros genes también pueden causar el trastorno. Kabuki syndrome Rara vez se hereda y se produce de forma espontánea.

En algunos casos, una genética síndrome puede ser el resultado de una mutación de novo y el primer caso en una familia. En este caso, se trata de una nueva mutación genética que se produce durante el proceso reproductivo.

Genes, ubicaciones y modos de herencia
Dominante autosómico
Recesivo ligado a X
Dominante ligado a X

¿Cuales son los principales síntomas de Kabuki syndrome?

El principal síntomas de Kabuki syndrome incluyen rasgos faciales característicos como cejas arqueadas, ojos muy separados o desalineados, punta nasal plana y orejas grandes. Una boca o mandíbula pequeña y un posible paladar hendido también son características de la condición genética.

Los defectos cardíacos congénitos pueden ser un síntoma de Kabuki syndrome. Otras condiciones de salud pueden incluir anomalías óseas (dedos cortos, escoliosis), hipotonía (tono muscular bajo), problemas de audición y / o pérdida de audición, problemas endocrinos, problemas dentales, convulsiones y epilepsia. La pubertad temprana en las niñas puede ser otra síntoma.

Individuos con Kabuki syndrome generalmente se les diagnostica algún grado de discapacidad intelectual y / o retraso en el desarrollo.

Posibles rasgos / características clínicas:
Hipodoncia, ceja muy arqueada, hirsutismo, paladar alto, punta nasal deprimida, laxitud articular generalizada, retraso global del desarrollo, estatura baja, estrabismo, microcefalia, hipotonía central, herencia dominante ligada al cromosoma X, estenosis pulmonar, columela corta, paladar hendido, nasal ancha punta, Defecto del canal auriculoventricular, Defecto del tabique auricular, Anormalidad del comportamiento, Anomalía de la mama, Convulsión, Almohadillas prominentes en las yemas de los dedos, Oreja protuberante, Diente natal, Hipoglucemia neonatal, Pestañas largas, Fisura palpebral larga, Hipotonía muscular, Ceja lateral escasa, Eversión tercio de los párpados inferiores, oreja ahuecada, disminución del peso corporal, maloclusión dental, braquidactilia, coartación de la aorta, dificultades de alimentación en la infancia

¿Cómo se hace la prueba a alguien? Kabuki syndrome?

La prueba inicial para Kabuki syndrome puede comenzar con la detección del análisis facial, a través de la plataforma FDNA Telehealth de telegenética, que puede identificar los marcadores clave del síndrome y describa la necesidad de realizar más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista. 

Sobre la base de esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.

Información médica sobre Kabuki syndrome

This is an intellectual disability syndrome with short stature and a characteristic face. Developmental delay is mild to moderate and some cases have austistic features (Ho and Eaves 1997). The main diagnostic feature, which is reminiscent of the make-up worn by actors in Kabuki theatre, is the presence of an everted lateral 1/3 of the lower lid and long palpebral fissures. Affected individuals have a broad nasal tip, prominent ear lobes and a cleft or high-arched palate. The 5th finger is short and there is persistence of the fetal finger pads. There are mild radiological changes in the vertebrae. Franceschini et al., (1993) reported a case with lower lip pits and idiopathic precocious puberty. Lip pits have also been reported by Kokitsu-Nakata et al., (1999), Makita et al., (1999) and Shotelersuk et al., (2002). The latter authors ruled out a microdeletion around the van der Woude syndrome locus. Breast development in female infants is common. Lerone et al., (1997) review features of ectodermal dysplasia in this condition. Other occasional features include neonatal teeth, conical teeth, missing permanent lower incisors and screwdriver shaped upper incisors (Mhanni et al., 1999), dislocated hips, nail hypoplasia, preauricular pits, sacral pits, anal abnormalities and renal defects. Canham (2006) added cutis aplasia of the scalp as a feature. Digillio et al., (2001) review the incidence of cardiac defects. 34% of patients from the literature had coarctation of the aorta and 31% VSDs. ASDs were seen in 16% of patients. Ho and Eaves (1997) reported four children with features of the condition, who showed autistic behaviour. Other occasional features include neonatal teeth, conical teeth, missing permanent teeth, and screw driver-shaped incisors (Mhanni et al., 1999; Matsune et al., 2001). There is a good review of the oral abnormalities by Petzold et al., (2003). Gabrielli et al., (2002) reported a case with growth hormone deficiency. Trigonocephaly can be a feature, and the case reported by David et al., (2004), was initially diagnosed as having C-trigonocephaly syndrome. A patient with a symptomatic Chiari I malformation was reported by Ciprero et al., (2005) and another by Ben-Omran and Teebi, (2005). These latter authors review the CNS malformations.
Niikawa et al., (1988) give an excellent review of 62 Japanese patients and Philip et al., (1992) and Schrander-Stumpel et al., (1994) report large series of non-Japanese cases, emphasising that joint hypermobility, ptosis and hypotonia appear to be more frequent in this group. Wilson (1998) reported thirteen cases and provides a good review. McGaughran et al., (2001) reported nine cases from New Zealand. Wessels et al., (2002) review 300 cases published in the literature up to 2001. Shotelersuk et al., (2002) report a good series of six cases from Thailand. Two had lip pits and there were discordant monozygotic twins. Kokitsu-Nakata and Guion-Almeida (2003) reported a case with unilateral microtia - presumably coincidental. Matsumoto and Niikawa (2003) provide a good review up to 2003.
Ming et al., (2003) reported three cases with Kabuki syndrome who also had a retinal coloboma. They provide a good review of eye abnormalities in Kabuki syndrome including Peters anomaly, micro or macrocornea, cataracts and optic nerve hypoplasia.
van Haelst et al., (2000) reported a case with stenosis of the major bronchi. Cardiac defects occur in about 50% of cases, and half of these will have a juxtaductal coarctation (Hughes and Davies, 1994).
Renal anomalies occur in 40-50% of cases and consist of horseshoe or duplex kidneys with reflux. Ewart-Toland et al., (1998) reported a case with sclerosing cholangitis. McGaughran et al., (2000) reported two cases with biliary atresia. Further cases with biliary atresia was reported by van Haelst et al., (2000) and Selicorni et al., (2001).
Chu et al., (1997) reported a possible case with a large temporoparietal subarachnoid cyst. Kasuya et al., (1998) reported a case with aqueduct stenosis. Di Gennaro et al., (1999) reported a case with seizures and polymicrogyria. Epilepsy occurs in 10-40% of cases (Ogawa et al., 2003), with grand mal and complex partial seizures being common. West syndrome was reported by Ito et al., (2007). In the 3 Finnish cases reported by Oksanen et al., (2004), all 3 had temporo-occipital spikes.Galan-Gomez et al., (1995) reported a case with a VI nerve palsy (Case 2). Yano et al., (1997) reported a possible case with brainstem and cerebellar atrophy. The case reported by Michi et al., (2002) with nodular heterotopic grey matter and a dysgenetic corpus collosum seems somewhat doubtful from the diagnostic point of view. In a long-term follow-up study Shalev et al., (2004) found that mild to moderate mental retardation persisted into adulthood. The notched eyebrows tended in fill in. Patients remained short, were obese, had relatively large heads and tapering fingers.
Ikegawa et al., (1993) reported three cases with recurrent dislocation of the patella. Fryns and Devriendt (1998) reported hypoplasia of the clavicles in a patient reported by Toutain et al., (1997). Kurosawa et al., (2002) reported four cases with this association.
Craniosynostosis may be an occasional feature. One of the cases reported by Niikawa et al., (1988) had increased digital markings and the case reported by Gillis (1990) had possible sagittal craniosynostosis. The case reported by Dallapiccola (1992) with a diagnosis of Baller-Gerold syndrome looked very much like she had Kabuki make-up syndrome. Ewart-Toland et al., (1998) also reported a case with craniosynostosis where the thumbs seemed small in the photographs. This case had markedly dysplastic kidneys requiring transplantation.
Say et al., (1993) reported a 13-year-old boy who had features of the condition with severe ossicular abnormalities of the middle ear (absent oval window, no stapedius tendon, a malformed incus and malleous). Mother was said to have similar facial features, but no photographs were shown. Igawa et al., (2000) reported three cases with dysplasia of the inner ear including cochlear abnormalities and Mondini dysplasia. Schrander-Stumpel et al., (1993) reported a 12-year-old girl with the condition who had also developed vitiligo.
Hostoffer et al., (1996) reported a case who developed immune thrombocytopenic purpura and acquired hypogammaglobulinemia with anti-IgA antibodies. Chrzanoska et al., (1998) reported a case with hypogammaglobulinemia but with a normal B-cell mitogenetic response and evidence of T-cell dysfunction. Patients with unusual features were reported by Genevieve et al., (2004). They included diarrhea, diaphragmatic defects, pseudoarthrosis of the clavicles, vitiligo, hypoglycemia and auto-immune thrombocytopenia. Autoimmune aspects of 19 patients were discussed by Ming et al., (2005), who found a high incidence of hypogammaglobulinemia (IgS and IgD), and increased frequency of autoimmune disorders. They reported a patient who died due to an idiopathic reaction to intravenous immunoglobulin therapy. Hypoglobulinemia A and G and trichrome vitiligo were reported by Zannolli et al., (2007). Merks et al., (2005) reported a patient who died because of a neuroblastoma and Shahdadpuri et al., (2008) had a case with a low-grade fibromyxoid sarcoma. Tumino et al., (2010) reported 2 patients, one with a hepatoblastoma and the other with a neuroblastoma.
Children with ring or marker X chromosomes can have a similar phenotype (Kajii et al., 1992; Dennis et al., 1993; McGinniss et al., 1997; Stankiewicz et al., 2001). Niikawa et al., (1988) found that three patients out of 62 studied had abnormalities of the sex chromosomes. One had a 45,X/46,X,r(X) and another had a 45,X/46,X,r(Y) karyotype. Wellesley and Slaney (1994) reported an affected 2-year-old girl with a 45,X karyotype and clinical features of Turner syndrome. Van Hagen et al., (1996) reported a convincing male case where the mother was found to be a low grade mosaic for a 45,X/46,XX karyotype. Interestingly the mother's sister and mother were also low grade mosaics.
Jardine et al., (1993) reported a possible case with an unbalanced 6;12 translocation. The breakpoints were at 6q25.3 and 12q24.31. This child was monosomic for part of 6q and trisomic for part of 12q. However, the features were not absolutely typical. Fryns et al., (1994) reported a case with a paracentric inversion of the short arm of chromosome 4 that was inherited from the mother. However no photographs of the patient were published. Lynch et al., (1995) reported monozygotic twins with convincing features of the condition. They had a pseudodicentric chromosome 13 which had been inherited from the normal mother. Galan-Gomez et al., (1995) reported a possible case with an apparently balanced 15/17 translocation (breakpoints not clear from the paper). The mother had the same karyotype.
Most cases of the condition are sporadic. Kobayashi and Sakuragawa (1996) reported a 17-year-old girl with the condition whose father was said to have the characteristic facial anomalies as well as the characteristic dermatoglyphics although he was of normal stature and above average intelligence. However no photographs of either of these individuals were published. Silengo et al., (1996) reported a case where the mother was said to have minor facial anomalies. In a subsequent pregnancy a fetus was found to have diaphragmatic hernia, which Silengo et al., (1996) interpret as being a feature of Kabuki syndrome. van Haelst et al., (2000) also reported a case with diaphragmatic hernia. Donadio et al., (2000) report a possible case with a diaphragmatic hernia and review other cases with this association from the literature. Tsukahara et al., (1997) reported two families where dominant inheritance of features of the Kabuki syndrome from the mother was quite convincing. A further affected mother and daughter were reported by Courtens et al., (2000), and a convincing mother-daughter pair by Pottinger et al., (2009).
Six patients with Kabuki and an 8p22-8p23 duplication, were reported by Milunsky and Huang (2003). No duplications were found in a large Japanese cohort - one of the authors of this paper was Niikawa whose name is associated with the syndrome. Others (Hoffman et al., 2005, Miyake et al., 2006), have failed to confirm this. However, Shieh et al., (2006) reported a case (they say not totally typical Kabuki) - but not bad (MB), with triplication of 8p22-p23. A patient with Kabuki reported by Maas et al., (2007) had a de novo 20p12 microdeletion taking out C20orf133. Exome sequencing of 10 patients revealed MLL2 mutations in 9, strongly suggesting that this is a major gene (Ng et al., 2010). In the study by Paulussen et al., (2011), of 45 clinically well-defined patients, 34 had MLL2 mutations. Hannibal et al., (2011) studied 110 patients - 74% had mutations. Facially, the 2 groups did not differ. Banka et al., (2012) looked at 116 patients and found mutations in 74. All those clinically ""spot-on"" had mutations. Those with feeding difficulties, kidney anomalies, early breast bud development, joint dislocations and palatal malformations were more likely to have mutations. Deletions (Lederer et al., 2012) and point mutations (Miyake et al., (2013) in KDM6A (at Xp11) which like MLL2 is a histone modifie can also cause the syndrome. Makrythanasis et al., (2013) found 45 mutations in a cohort of 86 patients.

Bögershausen et al. (2016) described a 14-year-old boy presenting with bilateral microphthalmia with orbital cysts and neonatal cholestasis with bile duct paucity. Large cystic lesions of the eyes were noted at birth. Orbital MRI evaluation showed bilateral microphthalmia and extraconal hyperintense multicystic lesions filling both orbital cavities. This constellation was consistent with a radiologic diagnosis of venous lymphatic malformation.

Badalato et al. (2017) described two sibling and their mother with characteristics overlapping Kabuki syndrome and CHARGE syndrome due to heterozygous missense mutation in the KMT2D gene. Clinical characteristics included choanal atresia, palatal abnormalities (uvula bifida, bifid palate, high palate), oligodontia, sensorineural hearing loss, clinodactyly, fetal finger pads, learning difficulties, and speech delay. Dysmorphic features were tall forehead, down-slanting palpebral fissures, anteverted nares, smooth philtrum, thin upper lip, and prominent chin.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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