Paula and Bobby
Parents of Lillie
What is Kabuki syndrome?
Kabuki syndrome is a rare genetic disorder and occurs in just 1 in 32,000 births. The condition affects males and females equally.
It is characterized by specific facial features, including arched eyebrows and wide-set eyes.
Health conditions associated with Kabuki syndrome may include short stature, immunological abnormalities, and elongated eyes, similar to those painted on the Japanese Kabuki theatre actors - hence the name. In medical terms, this eye form is called palpebral fissures with eversion of the lateral third of the lower eyelid. Up to half of the patients may present with congenital heart defects. Mid-moderate intellectual disability and developmental delay are also a feature of the syndrome.
Kabuki make-up syndrome, Kabuki syndrome, 1 KMS, Niikawa-Kuroki syndrome
What gene changes cause Kabuki syndrome?
Kabuki syndrome is a genetic condition caused by mutations in the KMT2D and KDM6A genes. Recent research suggests that mutations in other genes may also cause the disorder. Kabuki syndrome is very rarely inherited and occurs spontaneously.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
Genes, locations, and inheritance modes
What are the main symptoms of Kabuki syndrome?
The main symptoms of Kabuki syndrome include characteristic facial features such as arched eyebrows, wide-set or misaligned eyes, a flat nasal tip, and large ears. A small mouth or jaw and a possible cleft palate are also features of the genetic condition.
Congenital heart defects may be a symptom of Kabuki syndrome. Other health conditions can include bone abnormalities (short fingers, scoliosis), hypotonia (low muscle tone), hearing problems and/or hearing loss, endocrine issues, dental problems, seizures, and epilepsy. Early puberty in girls may be another symptom.
Individuals with Kabuki syndrome are usually diagnosed with some degree of intellectual disability and/or developmental delay.
Possible clinical traits/features:
Hypodontia, Highly arched eyebrow, Hirsutism, High palate, Depressed nasal tip, Generalized joint laxity, Global developmental delay, Short stature, Strabismus, Microcephaly, Central hypotonia, X-linked dominant inheritance, Pulmonic stenosis, Short columella, Cleft palate, Broad nasal tip, Atrioventricular canal defect, Atrial septal defect, Behavioral abnormality, Abnormality of the breast, Seizure, Prominent fingertip pads, Protruding ear, Natal tooth, Neonatal hypoglycemia, Long eyelashes, Long palpebral fissure, Muscular hypotonia, Sparse lateral eyebrow, Eversion of lateral third of lower eyelids, Cupped ear, Decreased body weight, Dental malocclusion, Brachydactyly, Coarctation of aorta, Feeding difficulties in infancy
How does someone get tested for Kabuki syndrome?
The initial testing for Kabuki syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on 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.
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