Kabuki Syndrome

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Kabuki Syndrome

In 1981, Niikawa and Kuroki independently described a pre- viously unrecognized mental retardation-malformation syndrome, characterized by a unique combination of craniofacial anomalies, congenital heart defects, skeletal anomalies, persist- ent fetal fingertip pads, dermatoglyphic abnormalities, mental retardation, and short stature. Because the peculiar facial appearance resembles the makeup of Kabuki actors in a tradi- tional Japanese theater, the Niikawa-Kuroki syndrome is also known as Kabuki or Kabuki makeup syndrome. The prevalence of the syndrome is estimated to be 1 in 32,000 live births in Japan. The syndrome is increasingly recognized in other parts of the world.

GENETICS/BASIC DEFECTS

1. Sporadic in most cases

2. Autosomal dominant inheritance suggested in a few fam- ilies

3. Other hypotheses

a. Postzygotic mutation, suggested by discordance between the twins, although multifactorial causes cannot be ruled out

b. Several instances of chromosomal abnormalities have been reported in the literature but without identical breakpoints in those autosomal abnormalities c. Microdeletion involving several contiguous genes,

suggested by sporadic cases in the majority of patients and a wide spectrum of clinical manifestations. So far, no chromosomal deletion was detected at the sites of the DiGeorge/velocardiofacial chromosomal region within 22q11.2 or flanking the van der Woude syndrome region at 1q32-q41

CLINICAL FEATURES

1. Craniofacial abnormalities

a. Peculiar facial appearance (100%): the most striking feature of the syndrome

i. Peculiar face that consists of eversion of the low lateral eyelid that is reminiscent of a Kabuki actor’s makeup and arched eyebrows with sparse- ness of their lateral one-third

ii. Long palpebral fissures iii. Depressed nasal tip

iv. Prominent, large ears b. Microcephaly (26%) c. Eye abnormalities

i. Long palpebral fissure (99%) ii. Lower palpebral eversion (92%) iii. Arched eyebrow (85%)

iv. Ptosis (50%) v. Epicanthus (46%) vi. Strabismus (36%) vii. Blue sclerae (31%)

d. Nasal abnormalities

i. Short nasal septum (92%) ii. Depressed nasal tip (83%) e. Ear abnormalities

i. Prominent ears (84%) ii. Malformed ears (87%)

iii. Preauricular dimple/fistula (22%) f. Oral abnormalities

i. High-arched palate (72%) ii. Abnormal dentition (68%) iii. Microganthia (40%)

iv. Cleft palate/lip (35%) v. Lower lip pit (27%) g. Low posterior hair line (57%) 2. Skeletal abnormalities (88%)

a. Pilonidal sinus (83%)

b. Short fifth middle phalanges (80%) c. Short fifth fingers (79%)

d. Joint laxity (74%)

e. Clinodactyly of fifth fingers (50%) f. Sagittal cleft of vertebral body (36%) g. Scoliosis (35%)

h. Short metacarpals (35%) i. Deformed vertebra/rib (32%) j. Foot deformity (24%) k. Spina bifida occulta (19%)

l. Hip dislocation (18%) m. Rib anomaly (18%)

n. Coarse carpal bone (17%) o. Cone-shaped epiphyses (13%) p. Patellar dislocation

3. Dermatoglyphic abnormalities a. Abnormal dermatoglyphics (96%)

i. Frequent fingertip ulnar loop patterns ii. Absence of digital triradius “c” or “d”

iii. An interdigital triradius “bc” or “cd”

iv. Fourth interdigital area patterns a) Hypothenar loop patterns b) Ulnar loop patterns

b. Presence of fingertip pads (89%): possible remnants of fetal pads

4. Neurologic abnormalities

a. Mild to moderate mental retardation (IQ<80) (84%) b. Hypotonia (68%)

c. Neonatal hypotonicity (28%) d. Seizures (17%)

e. Brain atrophy (4%) f. Retinal pigmentation (3%) 5. Short stature (55%)

6. Visceral abnormalities a. Cutaneous abnormalities

i. Hyperpigmented nevus (22%) ii. Generalized hirsutism (11%) 559

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560 KABUKI SYNDROME

b. Cardiovascular anomalies (42%) i. Ventricular septal defect ii. Atrial septal defect iii. Coarctation of the aorta

iv. Transposition of great vessels c. Gastrointestinal abnormalities

i. Umbilical hernia (9%) ii. Inguinal hernia (7%)

iii. Malrotation of the colon (6%) iv. Anal atesia/rectovaginal fistula (5%) d. Genitourinary abnormalities

i. Kidney/urinary tract malformations (28%) ii. Undescended testes (24%)

iii. Small penis (10%) 7. Other features

a. Susceptibility to infections i. Recurrent otitis media (63%)

ii. Repeat upper respiratory tract infections and pneumonias

iii. Single case reports

a) Severe immunodeficiency

b) Autoimmune hemolytic anemia and Poly- cythemia

c) Chronic idiopathic thrombocytopenia d) Acquired hypogammaglobulinemia with anti-

IgA antibody

b. Early breast development (28%) c. Hearing loss (27%)

d. Neonatal hyperbilirubinemia (20%) e. Obesity (19%)

f. Anemia (9%) g. Polycythemia (4%) h. Cystic fibrosis (2%)

i. Primary ovarian dysfunction (2%)

DIAGNOSTIC INVESTIGATIONS

1. Blood sugar during infancy for neonatal hypoglycemia (7%) 2. Thyroid profile for rare TBG deficiency (2%)

3. Growth hormone determination for rare growth hormone deficiency

4. Work up for autoimmune hemolytic anemia if present 5. Audiologic screening for hearing loss

6. Radiography for skeletal abnormalities a. Frequent features

i. Abnormalities of the spinal column a) Thoracic or lumbar scoliosis b) Sagittal cleft vertebra c) Narrow disc space d) Cervical ribs e) Schmorl node

ii. Dislocation of the hip joints iii. Abnormalities of the hands

a) Brachymesophalangy of the fifth fingers b) Short fifth metacarpals

c) Cone-shaped epiphysis of proximal phalanges II–V

b. Less frequent features i. Defective dentition

ii. Underpneumatized mastoids iii. Sacral spina bifida occulta

iv. Osteoporotic changes of the carpal bone and metacarpals

v. Underdeveloped ulnar styloids vi. Dysplastic acetabulum vii. Horseshoe kidney viii. Bifid renal pelvis

7. Renal ultrasonography for renal abnormalities 8. Echocardiography for congenital heart defects 9. MRI/CT scan for rare CNS anomalies 10. Dermatoglyphic analysis

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: low recurrence risk unless a parent has an autosomal dominant form of the syndrome b. Patient’s offspring: low recurrence risk unless the patient

has an autosomal dominant form of the syndrome 2. Prenatal diagnosis: none described to date

3. Management

a. Multidisciplinary approach to developmental delay and mental retardation

b. Hearing aids for hearing loss c. Treat infections

d. Growth hormone replacement therapy for growth hormone deficiency

e. Orthopedic intervention for scoliosis, dislocations, and foot deformities

f. Cardiac surgery for severe congenital heart defects g. Surgical repair of cleft lip/palate, gastrointestinal, and

anorectal anomalies

REFERENCES

Courtens W, Rassart A, Stene JJ, et al.: Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome. Am J Med Genet 93:244–249, 2000.

Digilio MC, Marino B, Toscano A, et al.: Congenital heart defects in Kabuki syndrome. Am J Med Genet 100:269–274, 2001.

Halal F, Gledhill R, Dudkiewicz A: Autosomal dominant inheritance of the Kabuki make-up (Niikawa-Kuroki) syndrome. Am J Med Genet 33:376–381, 1989.

Handa Y, Maeda K, Toida M, et al.: Kabuki make-up syndrome (Niikawa- Kuroki syndrome) with cleft lip and palate. J Craniomaxillofac Surg 19:99–101, 1991.

Kobayashi O, Sakuragawa N: Inheritance in Kabuki make-up (Niikawa- Kuroki) syndrome. Am J Med Genet 61:92–93, 1996.

Kuroki Y, Suzuki Y, Chyo H, et al.: A new malformation syndrome of long palpebral fissure, large ears, depressed nasal tip and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 99:570–573, 1981.

Kuroki Y, Katsumata N, Eguchi T, et al.: Precocious puberty in Kabuki make- up syndrome. J Pediatr 110:750–752, 1987.

Matsumoto N, Niikawa N: Kabuki make-up syndrome: a review. Am J Med Genet 117C:57–65, 2003.

Niikawa N, Matsuura N, Fukushima Y, et al.: Kabuki make-up syndrome:

a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 99:565–569, 1981.

Niikawa N, Kuroki Y, Kajii T: The dermatoglyphic pattern of the Kabuki make- up syndrome. Clin Genet 21:315–320, 1982.

Niikawa N, Kuroki Y, Kajii T, et al.: Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 31:565–589, 1988.

Schrander-Stumpel C, Meinecke P, Wilson G, et al.: The Kabuki (Niikawa- Kuroki) syndrome: further delineation of the phenotype in 29 non- Japanese patients. Eur J Pediatr 153:438–445, 1994.

Tsukahara M, Kuroki Y, Imaizumi K, et al.: Dominant inheritance of Kabuki make-up syndrome. Am J Med Genet 73:19–23, 1997.

Wessels MW, Brooks AS, Hoogeboom J, et al.: Kabuki syndrome: a review study of three hundred patients. Clin Dysmorphol 11:95–102, 2002.

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KABUKI SYNDROME 561

Fig. 1. A 12-year-old girl with Kabuki syndrome showing arched eye- brows, long palpebral fissures, everted lateral half of the lower eyelid, short nasal septum, post-cleft lip repair, prominent ears, and prominent finger pads.

Fig. 2. A one-year-old girl with Kabuki syndrome showing arched eyebrows, long palpebral fissures, short nasal septum, and hyper- trophic breasts. The infant also has cleft palate, large ears, and congenital hip dislocations.

Fig. 3. A one-year-old boy with Kabuki syndrome showing arched eyebrows, long palpebral fissures, everted lateral half of the lower eyelids, blue sclera, strabismus, short nasal septum, small chin, and large and prominent ears.

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562 KABUKI SYNDROME

Fig. 4. A 12-year-old boy with Kabuki syndrome showing character- istic facial features consisting of long palpebral fissures, arched eyebrows, bilateral lower lateral palpebral eversion, short nasal septum, high-arched palate, low hair line, and prominent finger pads. Other anomalies include mild mental retardation, neonatal hypotonia, recurrent otitis media and upper respiratory infections, joint laxity, ventricular septal defect, hip dysplasia, and short and clinodactyly of the 5th fingers.