Clin Genet 2004: 67: 209–219 Copyright # Blackwell Munksgaard 2004 Printed in Singapore. All rights reserved CLINICAL doi: 10.1111/j.1399-0004.2004.00348.x Mini Review Kabuki syndrome: a review

Adam MP, Hudgins L. Kabuki syndrome: a review. MP Adam and L Hudgins # Clin Genet 2004: 67: 209–219. Blackwell Munksgaard, 2004 Division of , Stanford University, Stanford, CA, USA Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa–Kuroki syndrome) is a multiple malformation/mental retardation syndrome that Key words: Kabuki make-up syndrome – was described initially in Japan but is now known to occur in many Kabuki syndrome – Niikawa–Kuroki syndrome other ethnic groups. It is characterized by distinctive facial features (eversion of the lower lateral eyelid, arched eyebrows with the lateral Corresponding author: Margaret Adam, one-third dispersed or sparse, depressed nasal tip, and prominent ears), M.D., Stanford University, Pediatrics/ skeletal anomalies, dermatoglyphic abnormalities, short stature, and Medical Genetics, 300 Pasteur Drive, mental retardation. A number of other manifestations involving other H-315, Stanford, CA 94305-5208, USA. Tel.: þ1 650 723 6858; organ systems can aid in the diagnosis and management of KS. This fax: þ1 650 498 4555; review will focus on the diagnostic criteria, the common and rare e-mail: [email protected] features of KS by organ system, and the possible etiology of this interesting condition. Received 28 April 2004, revised and accepted for publication 8 July 2004

Kabuki syndrome (KS) (Kabuki make-up syn- tations of KS and to discuss the possible underlying drome, Niikawa–Kuroki syndrome) is a multiple genetic etiology responsible for this condition. congenital anomaly/mental retardation syndrome that was first described simultaneously by two groups in Japan, Niikawa et al. (1) and Kuroki Prevalence et al. (2). They described a group of patients who had characteristic facial features, skeletal anoma- Based on a total of 10 patients identified in a lies, dermatoglyphic abnormalities, short stature, specific prefecture of Japan in a 16-year period, and mental retardation. Because the facial fea- the prevalence of KS in the Japanese population tures of the patients resembled the make-up of has been estimated to be 1/32,000 (3). Because all actors in Kabuki, the traditional Japanese play, of the initial reports originated from Japan, it was the term ‘Kabuki make-up syndrome’ was sug- thought that this condition was much more com- gested by Niikawa et al. (1). This condition has mon in the Japanese population. However, since also been referred to as the Niikawa–Kuroki 1981, there have been increasing reports of KS in syndrome, after the two groups who initially a wide variety of ethnic groups, including patients described it. However, the most common name of Northern European, Brazilian, Filipino, Viet- by which this condition is currently known in the namese, Arab, East Indian, Chinese, Mexican, literature is KS; the ‘make-up’ portion of the and African descent (4–12). Until recently, this original name has been discarded secondary to condition was almost certainly underdiagnosed concern that it might cause parental confusion outside of the Japanese population, and now or offense. that information about KS has become available The most striking aspects of KS are the unique worldwide, the true prevalence of this syndrome facial features, which usually prompt the clinician outside of Japan will hopefully be forthcoming. to consider this diagnosis. Patients often have long A recent article by White et al. estimated the palpebral fissures with eversion of the lateral one- minimal birth prevalence of KS in Australia and third of the lower eyelid, arched eyebrows with New Zealand to be 1/86,000 (13). However, they sparseness of the lateral one-third, short columella felt that this may actually be an underestimate of with depressed nasal tip, and prominent ears the prevalence of KS in their population because (Figs 1 and 2). There is also a range of other con- of under-recognition of the diagnosis. Based on genital anomalies and health-related issues, which the many reports from other populations, we accompany this syndrome. The purpose of this would presume that the prevalence will approxi- article is to review both common and rare manifes- mate that seen in the Japanese population.

209 Adam and Hudgins (eversion of the lower lateral eyelid, arched eye- brows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears) in 100% of their patients, skeletal anomalies (deformed spinal column with or without sagittal cleft vertebrae, and V) in 92% of their patients, dermatoglyphic abnormalities (fin- gertip pads, absence of digital triradius c and/or d, and increased digital ulnar loop and hypothenar loop patterns) in 93% of their patients, mild to moderate mental retardation in 92% of their patients, and postnatal growth deficiency in 83% of their patients. There have also been a number of less frequent findings reported in KS, including visceral abnormalities, premature breast develop- ment in females, and susceptibility to frequent infections. Table 1 summarizes some of the major and minor features found in KS. In the literature, there has been discussion as to whether the phenotype of KS varies based on ethnic background. Most authors agree that the facial phenotype of KS is easily recognizable in patients from all ethnic backgrounds (10, 11). The exception to this is a report of an American black male who had the external eyelid findings typical of KS without the arched eyebrows. The authors Fig. 1. Facial features of Kabuki syndrome. Note the long felt that his nasal configuration was heavily influ- palpebral fissures with lower lateral eyelid eversion, dispersed enced by his racial background, such that it was lateral one-third of the eyebrows, and widely spaced teeth. not classical for KS (14). This patient was excluded from the review of KS by Niikawa Diagnostic criteria et al. based on the fact that he lacked the char- acteristic facial features of KS (3). A follow-up Currently, there are no consensus diagnostic cri- letter from the original authors reaffirmed their teria for KS and there is no clinically available diagnosis in this patient and again suggested that genetic test to confirm the diagnosis. In 1988, the racial background of the patient obscured the Niikawa et al. reported on the clinical findings in full facial phenotype of KS in this instance (15). 62 patients diagnosed with KS (3). Based on the Other manifestations of this condition also findings in these patients, five cardinal manifesta- appear to vary somewhat based on ethnic back- tions were defined. These included a ‘peculiar face’ ground. Philip et al. reported findings in 16 non- Japanese patients with KS (10). In their review, 11/16 patients had significant neurological symp- toms aside from mental retardation, including and seizures, compared with only 8/ 62 patients reported by Niikawa et al. (3). Joint hypermobility also appeared to be more common in the non-Japanese population. This is sup- ported by data from Schrander-Stumpel et al. in which 29 non-Japanese patients were studied (16). In this group, again there appeared to be an increase in hyperlaxity and neurological problems including neonatal hypotonia, feeding problems, and . Wilson et al. similarly reported an increased incidence of neonatal com- plications, abnormal dentition, hypotonia, and microcephaly in non-Asian KS patients (17). Fig. 2. Profile of patient with Kabuki syndrome. Note the ear Despite these racial differences, it has been sug- pit and the short columella leading to a depressed nasal tip. gested that minimal criteria for the diagnosis of

210 Kabuki syndrome

Table 1. Summary of major and minor features of Kabuki Growth and feeding syndrome (KS) Patients with KS often demonstrate normal Patients with growth parameters at birth. However, most KS (cumulative Clinical feature percent)a patients develop failure to thrive and postnatal growth retardation during the first year of life, Major features which becomes more pronounced with age. It is Characteristic face 100 Long palpebral fissures 99 not uncommon for patients to have height 2 stand- Abnormal dermatoglyphics 96 ard deviations or more below the mean (20). Short nasal septum 92 Recently, a study by White et al. found that Persistent fingertip pad 89 over half of the patients with failure to thrive in Malformed ear 87 Arched eyebrows 85 infancy went on to develop an increased body IQ < 80 84 mass index or obesity in middle childhood or Prominent ears 84 adolescence (13). In support of this, Kluijt et al. Depressed nasal tip 83 described a male with KS who developed obesity Short 5th digit 79 Joint laxity 74 at age 13 despite a normal diet (21). Medical High-arched palate 72 practitioners should be aware of this increased Abnormal dentition 68 risk for obesity in adolescence and consider refer- Hypotonia 68 ral to a nutritionist, if necessary. Short stature (<2.0 SD) 55 Ptosis 50 Microcephaly is found in approximately one- quarter to one-third of patients with KS (5, 16, Minor features Cardiovascular anomaly 42 20). However, as mentioned previously, there Cleft lip and/or cleft palate 35 may be an increased incidence of microcephaly Scoliosis 35 in non-Japanese patients of up to 60% vs as low Deformed vertebra/rib 32 as 6% in Japanese patients (3, 17). However, head Blue sclerae 31 Kidney/urinary tract malformation 28 size does not appear to be a predictor of final Premature thelarche 28 developmental outcome in patients with KS (13). Hearing loss 27 Complete or partial growth hormone deficiency Lower lip pits 27 has been rarely reported (3, 22–24). At least two Cryptorchidism 24 Preauricular pits 22 of the patients reported with partial growth Hip dislocation 18 hormone deficiency had a somewhat efficacious Seizures 17 response to exogenous growth hormone therapy, aCumulative data for patients with KS are derived from with one patient’s height velocity increasing from Matsumoto et al. (20). 3.5 cm/year to 5.3 cm/year and another patient’s height velocity increasing from 3.6 cm/year to 11.2 cm/year after instituting growth hormone KS be as follows: long palpebral fissures with therapy (22, 24). Growth problems may be exa- eversion of the lateral portion of the lower eye- cerbated by feeding difficulties, which are quite lids; broad, arched eyebrows with lateral sparse- common (approximately 70%), gastroesophageal ness; short nasal columella with depressed nasal reflux, or malabsorption (18). Patients who exhi- tip; large, prominent or cupped ears; and devel- bit poorly coordinated suck and swallow may opmental delay or mental retardation (18). In require gastrostomy tube placement. addition, prominent fingertip pads are a frequent and relatively specific finding (19). In the authors’ Neurological experience, the majority of patients with KS have at least several of these features that lead to an As mentioned previously, hypotonia is a frequent overall gestalt suggestive of KS. The remainder of feature of KS and may be more common in non- this article will focus on both frequent and rare Japanese patients. This feature may be exacer- aspects of KS, , possible bated by joint hyperextensibility and tends to etiology, and prognosis. improve with age. The issue of an underlying neuromuscular abnormality in KS patients has been raised because of the observation that some patients with KS have ptosis, an expression- Manifestations by organ system less face, and a drooping lower lip. In a study by Table 2 summarizes the suggested evaluations Burke et al., dysarthria and dyspraxia were com- and management of patients with KS by organ mon features (11). When performed, muscle biop- system. sies in KS patients have been normal (10, 16). In

211 Adam and Hudgins

Table 2. Summary of suggested evaluations and management of patients with KS by organ system Organ system Evaluation Management

Growth and feeding Monitor height, weight, Consider referral to endocrinology if growth and head circumference velocity abnormal Consider pH probe study if there is evidence of gastroesophageal reflux Consider barium study in those with abnormal suck or swallow Consider gastrostomy tube placement in those with severe feeding difficulties Consider nutrition consult if patient develops obesity in later childhood Neurological Evaluate for hypotonia and seizures Consider referral to pediatric neurology Consider physical therapy evaluation for hypotonia Standard epileptic treatment for patients with seizures Otolaryngologic findings Follow expectantly for otitis media Consider ear, nose, throat (ENT) referral for and hearing chronic otitis media Annual hearing evaluations Amplification is indicated for those patients with hearing loss Craniofacial and dental Careful examination of palate at time Consider ENT referral in those with palatal issues of diagnosis Consider referral to orthodontics Dental evaluation as a toddler if or malocclusion detected Ophthalmologic Formal ophthalmology examination Any ocular abnormalities detected should at time of diagnosis be treated and/or followed by an experienced pediatric ophthalmologist Annual vision screening Cardiovascular Echocardiogram at time of diagnosis Referral to cardiology or cardiovascular surgery as indicated Respiratory Monitor for obstructive sleep apnea Consider a sleep study Consider referral to ENT Renal and genitourinary Renal ultrasound at time of diagnosis Consider referral to nephrology or urology, as indicated Careful physical examination for cryptorchidism Gastrointestinal (GI) Careful physical examination in Standard surgical correction of GI abnormalities neonates for GI anomalies Musculoskeletal Radiographs of the spine at diagnosis Consider referral to orthopedics for spinal abnormalities, Monitor for the development of scoliosis scoliosis, or recurrent joint dislocations Endocrinologic In females, follow expectantly for possibleExtensive endocrinologic workup for premature thelarche premature thelarche is unnecessary Immunologic/hematologic Monitor for frequent sinopulmonary Immunoglobulin levels in those patients with infections, multiple infections evidence of ITP, or autoimmune Consider referral to pediatric immunology hemolytic anemia Consider IVIG in those patients with documented immunodeficiency Development and behaviorMonitor developmental milestones Consider referral to a developmental pediatrician Psychoeducational testing in all or psychiatrist patients who Early intervention services should be instituted in infancy demonstrate cognitive difficulties In the older child, special education services may be warranted

ITP, idiopathic thrombocytopenic purpura; IVIG, intravenous administration of IgG. those patients with hypotonia, dysarthria, or dys- from the neonatal period up to 12 years of age praxia, physical therapy and speech therapy can (10, 18, 25). be helpful. Recently, Oksanen et al. reported three patients Approximately 10 to 39% of patients with KS who had bilateral spikes or polyspikes in the have seizures (16, 18). There does not appear to temporo-occipital regions on electroencephalo- be a specific seizure type associated with KS, grams (EEGs) (26). The authors suggested that although the majority of patients have localiza- such posterior focal spikes may be a typical find- tion-related epilepsy with a favorable seizure out- ing in KS, despite the fact that other EEG find- come (25). The age of onset of seizures can vary ingshavebeenreportedinpatientswithKS(18,25).

212 Kabuki syndrome tions in up to two-thirds of patients (3, 16). It should be noted that while frequent infections are common in KS, laboratory evidence of immune dysfunction has been documented only rarely (see section on Immunologic/hematologic). Hearing loss has been reported in up to 82% of patients ascertained through a multidisciplinary craniofa- cial clinic (31), but the true prevalence of hearing loss is probably closer to 20–30% (3, 10, 18, 20). Hearing loss has been characterized as conduc- tive, sensorineural, or mixed (11, 31, 32).

Craniofacial and dental In addition to the typical facial features men- Fig. 3. Female patient with Kabuki syndrome. Note the long tioned previously, Kawame et al. identified a palpebral fissures, bilateral ptosis (left greater than right), and prominent, cupped ears. unique configuration of the philtrum, which they described as trapezoidal in shape (18). By However, none of the patients reported by Oksa- this, they meant that the prolabium was flared nen et al. developed these EEG findings before as it met the upper portion of the vermilion the age of 8 years, and only two of the three border in some patients. patients had clinical seizures (26). Therefore, Cleft palate or cleft lip/palate has also been EEG studies done in early infancy or childhood described in approximately one-third of patients, might miss this finding. Further evidence for this while high arched palate has been seen in almost includes a report of a patient who developed two-thirds of patients (3, 11, 18, 20, 33, 34). seizure activity at the age of 10 years and was Burke et al. was the first group to suggest that also found to have polyspikes and polyspike/ KS is an underdiagnosed condition in the cleft slow wave complexes over the left temporo- lip/palate population (11). Lip pits have also been parietal region associated with bilateral occipital described in several patients with KS (7, 20, 35) polymicrogyria (27). Therefore, Oksanen et al. and will be discussed further under the section entitled Differential diganosis. suggested that disorders of cortical development, % including subtle abnormalities that might be Dental anomalies are seen in over 60 of missed with modern imaging techniques, could patients with KS (33). The most common finding be the cause of the EEG findings and seizures in is hypodontia, particularly of the central and lat- KS patients (26). eral incisors and the premolars. Other manifesta- Head-imaging studies in KS patients have often tions include malocclusion, microdontia, and a demonstrated non-specific cerebral atrophy or small dental arch. In addition, widely spaced enlarged ventricles (18). Major structural brain teeth with abnormal shape, including screw dri- abnormalities, including polymicrogyria, aque- ver-shaped incisors and conical teeth, have been ductal stenosis resulting in hydrocephalus, and described and may aid in the diagnosis (12, 33, 36, large arachnoid cyst requiring removal, have all 37). Maxillary recession and mid-face hypoplasia been rarely reported (27–30). may predispose patients with KS to the develop- ment of a small dental arch and malocclusion (33). Otolaryngologic findings and hearing Dysmorphic pinnae, otitis media, and hearing Ophthalmologic loss are some of the most common otolaryngolo- gic findings in KS (20, 31). Prominent, large, Ophthalmologic abnormalities have been found and cup-shaped ears characterize the type of ear in approximately one-third to one-half of patients dysmorphia (Fig. 3). Ear pits have also been with KS. The most common findings include described in approximately 20% of patients (16, ptosis, strabismus, and blue sclerae (Fig. 3) 18, 20) and can aid in the diagnosis. Otitis media (20, 21). Less common findings have included appears to be a frequent complication, which can refractive errors, delayed visual maturation with be exacerbated by the finding of cleft palate in nystagmus, Peters’ anomaly, palsy of the third approximately one-third of patients (18, 20) and cranial nerve, Marcus Gunn’s phenomenon by the finding of increased susceptibility to infec- (involuntary eyelid closure with jaw movement),

213 Adam and Hudgins cataracts, optic nerve hypoplasia, megalocornea, Diaphragmatic abnormalities have also been microcornea, and retinal and ocular colobomas rarely reported, including congenital diaphrag- (5, 18, 20, 21, 38–40). Because many of these matic hernia, eventration of the diaphragm, and findings have the potential to significantly impact paralysis of the diaphragm (6, 10, 19, 32, 44–46). vision, it has been suggested that all patients with Diaphragmatic abnormalities appear to be much KS undergo an initial ophthalmologic examin- more commonly found in non-Asian patients ation (21). (45).

Cardiovascular Renal and genitourinary In the original series of patients reported by Renal anomalies are present in over 25% of Niikawa et al. (1) and Kuroki et al. (2), only one patients with KS (20) and include malposition of patient was noted to have a congenital heart the kidneys, hydronephrosis, renal hypoplasia or defect that consisted of an atrial septal defect dysplasia, and fusion defects of the kidneys, such (ASD) and hypertrophic cardiomyopathy. Ohdo as horseshoe kidney (3, 5, 18). One patient with et al. was the first group to suggest that there may markedly dysplastic kidneys required transplan- be an increased incidence of congenital heart tation (47). Iwama et al. was the first group to defects in patients with KS (41). They reported report a patient with KS and ureter abnormal- on two patients with KS and heart defects. The ities, which consisted of a megaureter (48). Since first patient had a ventriculoseptal defect (VSD) then, duplication of the collecting system, ureter- which closed spontaneously and the second opelvic junction obstruction, and hydroureter patient had a complex heart defect consisting of have also been reported (18, 47). a double outlet right ventricle, a patent ductus Cryptorchidism has been reported in approxi- arteriosus, and a coarctation of the aorta. Since mately 25% and small penis has been described in that time, there have been many different conge- approximately 10% of males with KS (3, 5, 10, nital heart defects described in patients with KS 20). Hypospadias has also been reported in and the prevalence of heart defects in this popula- males (9). tion has been estimated to be between 28 and 80% (16, 39, 42), although the true incidence of such defects is more likely to be around 40–50% Gastrointestinal (18, 20, 31). The most common finding appears to Gastrointestinal abnormalities in KS are rare, be juxtaductal coarctation of the aorta, a rela- with an incidence of approximately 5% (3, 20). tively rare heart defect, followed by VSD and While malrotation of the intestines has been ASD (39, 43). Interestingly, coarctation of the reported in several patients (3, 29, 40), the major- aorta in KS appears to be much more common ity of patients have abnormalities of the anus or in males than in females. The sex distribution of rectum in the form of anal atresia, anovestibular VSD and ASD is not as straight forward, with fistula, or anteriorly placed anus (7, 18, 49). some authors noting an increased incidence of Biliary atresia has also been reported, as has both VSD and ASD in female patients with KS neonatal sclerosing cholangitis that required a and other authors finding no sex difference (39). liver transplantation (20, 32, 47).

Respiratory Musculoskeletal Respiratory abnormalities in KS are relatively Skeletal abnormalities are common in KS and are uncommon, although Peterson-Falzone et al. used as part of the diagnostic criteria for this reported airway problems in 58% of patients condition. The initial reports by Niikawa et al. who presented to a multidisciplinary craniofacial (1) and Kuroki et al. (2) sited short and incurved clinic (31). Recurrent pneumonia appeared to be fifth digits with short fifth metacarpals, cone- the most common problem, but this may actually shaped epiphyses of the proximal second through be related to immune dysfunction, which will be fifth phalanges, dislocation of the hip joints, and discussed in a separate section, as opposed to true various vertebral anomalies (butterfly vertebra, airway abnormalities. Obstructive sleep apnea sagittal cleft, narrow intervertebral disc space, requiring either tonsillectomy or tonsillectomy and scoliosis). Cranial abnormalities including with adenoidectomy was found in several coronal synostosis, metopic synostosis, incom- patients. Two patients have been reported with plete development of the frontal and/or maxillary stenosis of the central airways (32). sinuses, digital impression of the skull, and

214 Kabuki syndrome common finding, which is present in about one- quarter of females with KS, is isolated premature thelarche, with breast development as early as 4 months of age (3, 10, 20, 22, 52, 53); however, true central precocious puberty has also been rarely reported (28, 35, 53). Pescovitz et al. theo- rized that premature thelarche and central preco- cious puberty represented different ends of the spectrum of precocious activation of the hypotha- lamic luteinizing hormone-releasing hormone (LHRH) neurons (54). Not surprisingly, elevated gonadotropin levels, particularly isolated Fig. 4. Fingertip pads in an infant with Kabuki syndrome. increases in follicle-stimulating hormone (FSH), have been reported in KS patients with either underdevelopment of the mastoid processes have premature thelarche or central precocious pub- been found in a handful of patients (3, 18, 47). erty (35, 53). Although the underlying etiology Joint hypermobility is seen in one-half to three- for the precocious sexual maturation is unknown, quarters of patients, and joint dislocations are not Kuroki et al. postulated that it could be second- uncommon, particularly of the hips, patellae, and ary to low hypothalamic sensitivity to the sup- shoulders (18, 20, 50). Procollagen studies in at least pressive effects of sex hormones on gonadotropin one patient were normal (18). The finding of joint secretion (53). hypermobility tends to improve with age. Inguinal Growthhormonedeficiency,hypoglycemia,con- andumbilicalherniashavealsobeenreportedin genital hypothyroidism, and insulin-dependent approximately 10% of patients (3, 10, 20). diabetes mellitus are all rare findings in KS (3, 13, 18, 20, 22, 52, 55), and at least one patient has been reported with primary ovarian dysfunction Dermatoglyphics resulting in markedly delayed sexual development Over 90% of patients with KS have unusual (38). dermatoglyphic patterns, including fingertip ulnar loop patterns, absence of digital triradius ‘c’ or ‘d’, interdigital triradius ‘bc’ or ‘cd’, Immunologic/hematologic hypothenar loop patterns, and ulnar loop pat- An increased susceptibility to infections has been terns in the fourth interdigital area. In addition, reported in approximately 60% of patients with the vast majority of patients have also been found KS (3, 16). In particular, KS patients have a to have persistent fingertip pads (Fig. 4), which propensity to the development of otitis media, are clue to the diagnosis (1–3, 20, 51). upper respiratory tract infections, and pneumo- nia. It is unclear whether the otitis media is truly Ectodermal secondary to an underlying immunologic abnormality or whether it is related to the finding Aside from dental abnormalities which have of cleft palate or other craniofacial abnormalities, already been discussed in the section entitled such as Eustachian tube anomalies, that could Craniofacial and dental,patientswithKScan predispose to middle ear infections (9). However, have other abnormalities of the hair and nails simi- recurrent otitis media has been reported in a lar to findings in patients with various types of number of patients without cleft palate (31). ectodermal dysplasias. Specifically, absent, hypo- Severe immunodeficiency with hypogammaglo- plastic and/or fragile nails, brittle hair with trichor- bulinemia requiring intravenous administration rhexis nodosa, twisting of the hairshafts, of IgG (IVIG) has been reported in several irregularity of the hair diameter, and congenital patients (18, 56, 57). In addition, acquired hypo- alopecia areata have been noted (5, 6, 8, 11, 37, 52). gammaglobulinemia with anti-IgA , In addition, hypopigmented and hyperpigmented autoimmune hemolytic anemia, polycythemia, skin lesions have been rarely reported (5, 52). and idiopathic thrombocytopenic purpura (ITP) have each been rarely reported (3, 18, 52, 57). There has also been one report of a patient with Endocrinologic IgA deficiency which was felt to manifest as an A number of endocrinologic abnormalities have autoimmune disease consisting of both Hashi- been described in patients with KS. The most moto thyroiditis and vitiligo (47).

215 Adam and Hudgins One patient has been reported with low levels of Differential diagnosis IgG and IgA, a history of recurrent infections, and There are a number of genetic syndromes that pre-B-cell acute lymphoblastic leukemia (46). The each shares some characteristics with KS. authors speculate that immunodeficiency in KS Patients with 22q11 deletion syndrome (velo- might predispose patients to the development of cardiofacial syndrome, DiGeorge syndrome) malignancies. However, further studies evaluating can have cleft palate, cardiac malformations, this possible association need to be performed. and renal anomalies, which are all features that can be seen in KS. However, when evaluated, Development and behavior patients with KS have not been found to have microdeletions in the 22q11 region, making a Mental retardation, defined as an intelligence common etiology and pathogenesis for these quotient (IQ) of <70, is considered a cardinal two disorders unlikely (43, 56, 60). manifestation of KS. In a review of 62 patients Patients with KS can have clinical features in with KS by Niikawa et al., 92% had some degree common with patients who have van der Woude’s of mental retardation (which they defined as an syndrome (VWS), an autosomal dominant condi- IQ of <80), mainly in the mild to moderate range tion in which cleft lip/palate, lip pits, and hypo- (3). Of the patients without mental retardation, dontia are found. In 1999, however, Makita et al. all patients had an IQ of 83 or less. Since the time demonstrated that KS was not caused by a micro- of that review, there have been multiple reports of deletion in the VDS1 critical region on chromo- patients with KS and normal intelligence (5, 30, some 1q32–q41 (23). 33, 58), such that a more recent review by Matsu- One of the more unusual features of KS is the moto et al. estimates that one-sixth of patients persistent fingertip pads. This feature has also with KS have normal intelligence (20). However, been reported in FG syndrome, Rubinstein– there have also been reports of more severely Taybi syndrome, Fryns syndrome, and Weaver affected individuals, including individuals with syndrome (19). However, the distinctive facial IQs of <35 (8, 38, 50). No consistent cognitive features of KS should allow one to distinguish it pattern has been described in KS but a decline in from these other conditions. IQ over time has been rarely reported (8, 38). KS and Turner’s syndrome also share many Patients with KS appear to have particular features, including a propensity for patients to delays in speech and language acquisition as have coarctation of the aorta. In fact, there have well as articulation abnormalities. Articulation been multiple reports of patients with KS or problems may be exacerbated by oral-motor KS-like features and either abnormalities of the hypotonia, poor coordination, and craniofacial X chromosome or 45,X cell lines, which will be anomalies (11, 59). A recent study of speech char- discussed further in the next section (3, 61–64). acteristics by Upton et al. demonstrated that pitch, loudness, and prosody did not mature over time in two adolescent patients despite Etiology, pathogenesis, and genetics improvements in articulation (59). Therefore, maturation of speech characteristics may be The cause of KS is currently unknown. Numer- delayed or absent in KS patients, making speech ous cytogenetic abnormalities have been noticeably different from adolescent peers. reported in patients with KS or KS-like features, Several patients have been found to have autism including an interstitial duplication of 1p or autistic-like behavior, with difficulties in both [dup(1)(p13.1p22.1)], an inherited balanced communication and peer interactions (8, 26). translocation between chromosomes 3 and 10 However, a recent study of 27 patients with KS [t(3;10)(p25;p15)], an inherited paracentric revealed good socialization skills, ease with strang- inversion of the short arm of chromosome 4 ers, and an affable nature despite the existence of [inv(4)(p12pter)], a partial 6q monosomy with poor eye contact (13). In addition, parents of these partial 12q trisomy [der(6)t(6;12)(q25.3;q24.31)], patients reported excellent long-term memory for an inherited pseudodicentric chromosome 13, an faces, music lyrics, events, and dates. Many inherited balanced translocation involving 15q patients appeared to have a particular love of and 17q [t(15;17),(15q;21q)], a pericentric inver- music with musical aptitude outside that found sion of the Y chromosome, ring Y, ring X, and in their families. In several children, music proved 45,X (3, 39, 42, 61–68) (Table 3). However, the to be an excellent tool to teach new concepts or only cytogenetic abnormalities that have been skills. Knowledge of this may help parents and found repeatedly are those that involve the X teachers devise more effective educational plans chromosome, which have led some authors to for patients with KS. postulate that KS may be due to abnormalities

216 Kabuki syndrome

Table 3. List of previously reported chromosome anomalies of this duplication. Because of these findings, in patients with Kabuki syndrome (KS) or KS-like features Milunsky et al. felt that this duplication could Chromosome aberration De novo/familial Reference represent a common etiology for KS (72). To date, at least one KS patient has been dup(1)(p13.1p22.1) De novo (65) t(3;10)(p25;p15) Familial (39) reported without any aberration found on CGH inv(4)(p12pter) Familial (66) (46), and recently, 28 patients with typical KS did der(6)t(6; 12)(q25.3;q24.31) De novo (67) not have any detectable duplication of the 8p22– dup 8p22–8p23.1 De novoa (72) 8p23.1 region by FISH (73). Miyake et al. spec- psu dic(13) Familial (68) t(15;7)(15q;1q) Familial (42) ulate that perhaps the patients studied by inv(Y)(p11.2q11.23) Familial (3) Milunsky et al. had either atypical KS or possibly 45X,r(X)(p11.2q13) or r(Y) Not stated (3) an ‘8p23.1–p33 duplication syndrome’ with (p11.2q11.2) features similar to KS (73). Therefore, further 45X/46,X,r(X) Presumably (62, 64) de novo studies will need to be done to confirm this asso- 45X/46,X,r(X)(p11.2q13) Presumably (63) ciation and to more fully evaluate this chromoso- de novo mal region in order to define the underlying 45, X Presumably (61) genetic etiology of KS. Certainly, it is possible de novo that KS is a heterogeneous disorder and abnor- aTwo parents of two different KS patients with this duplication malities not only on chromosome 8, but also on were found to have a heterozygous inversion at 8p23.1. other chromosomes, such as the X chromosome, could lead to similar KS features. involving the pseudoautosomal region of the X chromosome (3, 39). Interestingly, Matsumoto Prognosis/natural history et al. pointed out that those patients with KS-like features and ring X tend to have more severe KS was only recently recognized as a genetic manifestations than is typical for KS without syndrome; therefore, a complete study of the nat- ring X (20). Therefore, they postulated that ring ural history of this condition has not been per- X may lead to KS-like features but is most likely formed. It appears that the facial features of KS causally different from KS. may evolve over time, such that the diagnosis is The majority of cases of KS are sporadic and difficult to make in the neonatal period (10, 11). the sex ratio is nearly equal. A recent review by Similarly, it is unclear whether continued evolu- Matsumoto et al. found the male-to-female ratio tion of the phenotype may also make the diagno- among 251 patients with KS to be 1.16 : 1 (20). sis difficult in adulthood, particularly in those A number of familial cases have been reported, patients who are more mildly affected. This may which document vertical transmission of KS or lead to an ascertainment bias in the literature for KS-like features from mothers to sons and those patients with more severe manifestations. daughters and father to daughter (5, 6, 44, 58, Because KS is not typically associated with 69, 70). Two pairs of monozygotic twins have severe medical complications, it is presumed that been reported; in one pair, the twins were con- the prognosis for survival into adulthood is good, cordant for KS and in the other pair, the twins particularly if congenital anomalies, such as where discordant for KS (68, 71). For the discord- congenital heart defects, and infections are prop- ant pair, a postzygotic mutation in the affected erly managed in childhood. Reports of vertical twin could have led to the condition, but multi- transmission of KS from both females and factorial inheritance cannot be ruled out. Given males imply that fertility may not be affected by the number of familial cases, autosomal domin- this condition. ant inheritance seems likely. Recently, using comparative genomic hybrid- Conclusions ization (CGH) and fluorescence in situ hybrid- ization (FISH), Milunsky et al. reported a KS is a multiple malformation/mental retarda- duplication of 8p22–8p23 in six unrelated patients tion syndrome characterized by distinctive facial with KS (72). The duplicated region was found to features (eversion of the lower lateral eyelid, be approximately 3.5 Mb in size. This duplication arched eyebrows with the lateral one-third dis- was not found in two parents or in 20 control persed or sparse, depressed nasal tip, and promi- individuals. Two mothers of KS patients and one nent ears), skeletal anomalies, dermatoglyphic control individual were found to have a hetero- abnormalities including persistent fingertip pads, zygous submicroscopic inversion involving mild to moderate mental retardation, and post- 8p23.1, which may contribute to the occurrence natal growth deficiency. A number of visceral,

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