American Journal of Medical Genetics 73:19–23 (1997)
Dominant Inheritance of Kabuki
Make-Up Syndrome
Masato Tsukahara,1* Yoshikazu Kuroki,2 Kiyoshi Imaizumi,2 Yoichiro Miyazawa,3 and
Kiyosato Matsuo4
1
School of Allied Health Sciences, Yamaguchi University, Ube, Yamaguchi, Japan
2
Division of Medical Genetics, Kanagawa Children’s Medical Center, Kanagawa, Japan
3
Department of Pediatric Cardiology, Kanagawa Children’s Medical Center, Kanagawa, Japan
4
Department of Pediatrics, Sanyo General Hospital, Sanyo-Cho, Yamaguchi, Japan
We report on a total of 4 individuals in 2
families with Kabuki make-up syndrome. In
family 1, the proposita, a 2 4/12-year-old girl
and her mother had typical Kabuki make-up
syndrome. The proposita also had early
breast development. In family 2, the
proposita, a 6-month-old girl and her
mother had typical Kabuki make-up syn-
drome. The proposita died at age 6 months.
Analysis of 2 families indicates that the
condition is an autosomal dominant inheri-
tance with variable expressivity. Am. J.
Med. Genet. 73:19–23, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: dominant inheritance; famil-
ial occurrence; Kabuki make-
up syndrome
INTRODUCTION
Kabuki make-up syndrome (Niikawa-Kuroki syn-
drome), first described the same year independently by
Niikawa et al. [1981] and Kuroki et al. [1981], is char-
acterized by mild to moderate mental retardation, post-
natal growth retardation, unusual face, fingertip pads,
and minor skeletal, dermatoglyphic, and urogenital ab-
normalities. Unusual facial anamolies involve arched
eyebrows with sparse or dispersed lateral half, long
palpebral fissures, eversion of the lower lateral eyelids,
long eyelashes, epicanthus, depressed nasal tip, short
nasal septum, large and prominent ears, and micro-
gnathia. Skeletal and dermatoglyphic abnormalities
Contract grant sponsor: The Ministry of Education, Science,
Sports and Culture of Japan; Contract grant number: (C)
08670892; Contract grant sponsor: The Ministry of Health and
Welfare of Japan.
*Correspondence to: Masato Tsukahara, M.D., School of Allied
Health Sciences, Yamaguchi University, Ube, Yamaguchi-Ken
755, Japan.
Received 8 January 1997; Accepted 9 May 1997
© 1997 Wiley-Liss, Inc.
include scoliosis, cleft vertebrae, short 5th fingers, in-
crease of fingertip ulnar loops, absence of digital trira-
dii c and d, and hypothenar loop patterns. Other incon-
sistent but important findings are early breast devel-
opment in infant girls, congenital heart defects,
abnormal dentition, cleft palate or cleft lip and palate,
and preauricular dimple.
More than 70 Japanese individuals with the syn-
drome have been reported [Niikawa et al., 1988; Handa
et al., 1991; Oguni et al., 1993; Kobayashi and
Sakuragawa, 1996]. As for non-Japanese individuals
with the syndrome, at least 90 such instances have
been recorded [Galán-Gómez et al., 1995; for refer-
ences; Meinecke and Rodewald, 1989; Jardine et al.,
1993; Devriendt and Fryns, 1994; Fryns et al., 1994;
Schrander-Stumpel al., 1994; Wang et al., 1994; Welle-
sley and Slaney, 1994; Ilyina et al., 1995; Lynch et al.,
1995; Silengo et al., 1996; Li et al., 1996]. In view of the
increasing number of the non-Japanese individuals
with the syndrome reported, the earlier perception of
low incidence of the syndrome outside of Japan re-
quires modification.
Most of the individuals reported with the syndrome
have been sporadic, with the exception of 3 families, in
each of which a parent had an incomplete form of the
syndrome [Halal et al., 1989; Kobayashi and
Sakuragawa, 1996; Silengo et al., 1996].
We describe here 2 Japanese families in each of
which the mother had a complete form of the syndrome
and transmitted the disorder to a daughter.
CLINICAL REPORTS
Family 1
The proposita is a 2 4/12-year-old Japanese girl. She
was born to a healthy and nonconsanguineous 23-year-
old, G2P1 mother and a 31-year-old father at 39 weeks
of gestation after an uneventful pregnancy. Birth
weight was 2,560 g. Apgar scores were 6 and 9 at 1 and
5 minutes, respectively. She was treated intravenously
with antibiotics for 3 days because of cloudy amniotic
fluid. Chest radiography showed a mass in the right
anterior mediastinum. She was transferred to us at age
7 days because of abdominal distension and tachypnea.
20 Tsukahara et al.

On admission, she was tachypneic (70–90/min), and

intubated for 10 days because of respiratory failure.
She was treated with diuretics and digoxin. Cardiac
systolic murmurs with a gallop rhythm were audible.
Echocardiography and cardiac catheterization docu-
mented postductal coarctation of the aorta, an atrial
septal defect, and mitral stenosis. She had a cleft soft
palate. Skeletal survey showed hypoplasia of the 5th,
10th, and 11th thoracic vertebrae. Ultrasonography
and CT scan of the abdomen indicated the mass in the
right anterior mediastinum to be a liver herniated
through a partial defect of the right diaphragma. Brain
CT scan showed colpocephaly.
The cleft soft palate was repaired at age 20 months.
Early breast development (Tanner stage II) was noted
at age 1 3/12 years. At age 2 years, serum estradiol
level was 10.0 pg/ml (normal range; less than 10 pg/
ml), serum LH 0.29 mIU/ml (normal range; 0.1–0.4
mIU/ml), and serum FSH 9.3 mIU/ml (normal range;
1.4–9.3 mIU/ml). Her psychomotor development was
delayed. She held her head up at age 4 months, rolled
over at 8 months, sat alone at 12 months, spoked mean-
ingful words at 13 months, and walked alone at 21
months.
When evaluated at age 2 4/12 years, She weighed
9.07 kg (−2.0 S.D.), measured 75.5 cm (−3.1 S.D.), had
an occipitofrontal circumference (OFC) of 46.8 cm (−0.6
S.D.), and a span length of 76.1 cm. She had a low
posterior hair line, long palpebral fissures, lower pal-
pebral eversion, hypertelorism, epicanthal folds, a
short nose with a hypoplastic nasal septum, and promi-
nent and simple earlobes (Fig. 1). She had enlarged
breasts, short 5th fingers, fingertip pads, and a sacral
dimple. Serum estradiol was high (141.1 pg/ml). The
serum LH and FSH responses to LH-RH loading (100 Fig. 1. The proposita of family 1 showing characteristic facial appear-
mg/m2 intravenous injection) were hyperactive. The ance and early breast development.
basal and peak LH levels were 0.74, and 7.84 mIU/ml,
respectively, and FSH levels were 4.41, and 42.56 mIU/ was 153. Chromosomes were normal (46,XX, high-
ml, respectively (TR-FIA method). Other endocrine resolution G-banded).
survey was normal, including serum somatomedin C, The father was phenotypically normal. The elder sis-
ACTH, urinary growth hormone, cortisol, T3, T4, and ter, born at 41 weeks of gestation with a birth weight of
TSH. Ultrasonography of the abdomen showed no ab- 2,470 g, was phenotypically and mentally normal.
normalities.
Dermatoglyphics were as follows: axial triradii at the Family 2
t position; right hand: Lu, Lr, Lu, W, Lu; left hand: Lu,
W, Lu, Lu, Lu. Total finger ridge count was 69. Lym- The proposita in this family is a 6-month-old girl.
phocyte chromosomes were normal (46,XX, high reso- She was born at 42 weeks of gestation to a 31-year-old,
lution G-banded). The liver and renal function tests primigravid mother and a 37-year-old father, both
were normal. Her developmental quotient (DQ) was 74. healthy and unrelated. Birth weight was 2,715 g. When
The mother, 27 years old at evaluation, weighed 41 she was referred to us soon after birth, her activity and
kg (−1.7 S.D.), measured 149.4 cm (−1.6 S.D.), had an sucking were poor, and her cry was weak. She had
OFC of 53.3 cm (−1.5 S.D.) , and a span of 146.3 cm. She tachypnea, pale skin color, and mild cyanosis of the lips
was reported to had been toilet-trained at age 3 years. and nailbeds. Heart murmurs were audible. She had
At age 9 years, her cleft soft palate was operated. She long palpebral fissures, lower lateral palpebral ever-
graduated from high school. She was very quiet, and sion, strabismus, long eyelashes, prominent ears, a de-
spoke only when asked questions. She had a low pos- pressed nasal tip, and micrognathia (Fig. 3). She had
terior hair line, eyebrows with dispersed lateral half, fingertip pads. At 22 days of life, she was operated on
long eyelashes, long palpebral fissures, eversion of the with anastomosis between the ascending aorta and
lower lateral palpebrae, a high nasal root, prominent main pulmonary trunk, coarctation of the oriface of the
ears, and thin vermilion border of the upper lip (Fig. 2). main pulmonary trunk, and atrial septostomy. Despite
She had short 5th fingers. Dermatoglyphics were: axial the operation, heart failure progressed steadily, and
triradii at the t position; right hand: Lu, W, W, W, Lu; she died at 6 months of cardiac and multiple organ
left hand: Lu, W, Lu, Lu, Lu. Total finger ridge count failure.
 Kabuki Make-Up Syndrome 21

Fig. 2. The proposita’s mother of

family 1.

The proposita’s mother had Kabuki make-up facial
appearance. Her mentality was borderline (I.Q. 82).
Her job after graduation from high school was simple
manual work. She was a very quiet person of few
words. She measured 138 cm (−3.9 S.D.). She had long
palpebral fissures, lower palpebral eversion, arched
eyebrows with sparse lateral half, long eyelashes,
lower palpebral eversion, short nasal septum with de-
pressed nasal tip, and prominent and malformed ears.
Both of her 5th fingers were short and incurved, and
obvious finger tip pads were observed. She had neither
congenital heart defect nor other visceral anomalies.
Photo permission of the mother was not obtained. The
proposita’s father was phenotypically and mentally
normal.
DISCUSSION
In each family we described, both the proposita and
the mother had clinical manifestations consistent with

Fig. 3. The proposita of family 2 at autopsy showing characteristic facial appearance.

22 Tsukahara et al.

the Kabuki make-up syndrome (Table I). They included
short stature, characteristic facial appearance, cleft
palate (proposita and mother of family 1), early breast
development (proposita of family 1), congenital heart
defect (proposita of family 1 and 2), fingertip pads
(propositas of family 1 and 2, mother of family 2), and
skeletal anomalies (proposita of family 1).
No consistent causal factor has been identified in the
Kabuki make-up syndrome. Chromosome abnormali-
ties in association with Kabuki make-up syndrome
have been reported. Niikawa et al. [1988] reported 3
patients with structural sex chromosomal abnormali-
ties, including a pericentric inversion of Y chromosome,
and a ring or X chromosome, and suggested the possi-
bility of pseudoautosomal dominant inheritance. Jar-
dine et al. [1993] reported a child with features of the
Kabuki make-up syndrome who had partial 6q mono-
somy/partial 12q trisomy. However, this case does not
seem to be affected with Kabuki make-up syndrome.
Fryns et al. [1994] reported on a 3-year-old girl with
the Kabuki make-up syndrome and her healthy
mother, both having paracentric inversion of 4p,
46,XX,inv(4)(p12pter). Whether or not the mother has
some of phenotype of the Kabuki make-up syndrome is
unknown because the detailed clinical description was
not obtained in this report. In our cases, chromosome
analyses were normal and paracentric inversion of 4p
was not detected. Some phenotypic overlap between
Kabuki make-up syndrome and Turner syndrome has
also been reported [Niikawa et al., 1988; Kajii et al.,
1992; Wellesley and Slaney, 1994].
Most of reported patients has been sporadic. Familial
occurrence in our 2 families suggests autosomal or X-
linked dominant inheritance. Autosomal dominant in-
heritance of this condition was suggested by Kuroki et
al. [1981], McKusick [1986], and Niikawa et al. [1988].
Familial occurrence of the Kabuki make-up syn-
drome was reported 3 times. Halal et al. [1989] re-
ported a familial occurrence of Kabuki make-up syn-
drome in which father, and his son and daughter were
affected, suggesting autosomal dominant inheritance.
Kobayashi and Sakuragawa [1996] also reported a
family in which father and his daughter were affected.
Silengo et al. [1996] reported an Italian girl with typi-
cal findings of the Kabuki make-up syndrome and a
mildly affected mother. Furthermore, the facts that
both sexes are equally affected, [Niikawa et al., 1988;
Schrander-Stumpel et al., 1994], the consanguinity
rate is not significantly high [Niikawa et al., 1988],
facial resemblance in the parents or relatives of pa-
tients has been reported [Sheikh et al., 1986; Niikawa
et al., 1988; Kuroki, 1993; Say et al., 1993; Schrander-
Stumpel et al., 1994; Ilyina et al., 1995], a pair of twins
concordant for the syndrome [Lynch et al., 1995], and
the condition was inherited vertically and the clinical
manifestations varied in familial cases, are compatible
with autosomal dominant inheritance. Altogether, it
seems that the condition is inherited as an autosomal
dominant trait with variable expressivity, and sporadic
cases may represent fresh mutation. Our cases also
demonstrate that affected mothers with the Kabuki
make-up syndrome may be fertile.
In conclusion, the condition may be autosomal dom-
inant inheritance with variable expressivity, and we
suggest that subtle signs of Kabuki make-up syndrome
must be searched for in parents of affected children.

TABLE I. Clinical Manifestations in Kabuki Make-Up Syndrome

Proposita
Age (yrs) 2 4/12
Sex
Short stature
IQ or mental retardation
Low posterior hair line
Long palpebral fissures
Arched eyebrows, sparse
in lateral half
Epicanthus
Strabismus
Lower palpebral eversion
Short nasal septum
Prominent ears
Malformed ears
Preauricular dimple
Depressed nasal tip
High arched palate
Cleft palate
Abnormal dentition
Spaced teeth
Micrognathia
Finger pads
Short 5th finger
Deformed vertebra
Heart defect
Early breast development
Family 1 Family 2
Mother Proposita Mother
27 6/12 31
F F F F
+ + + +
+ ± + ±
+ + − −
+ + + +
+ + + +
+ + − −
− + − −
+ + + +
+ − + +
+ + + −
+ − + +
− − − −
− − + +
− − − −
+ + − −
− − − −
− − − −
− − + −
+ − + +
+ + + +
+ ? − ?
+ − + −
+ − − −

ACKNOWLEDGMENTS
We thank Drs. T. Somei, F. Kishi, T. Hayashi, and H.
Yoshii for their contributions to the management of
family 1. This work was supported in part by Grant-
in-Aid for Scientific Research (C) 08670892 from The
Ministry of Education, Science, Sports and Culture of
Japan (M.T.) and by a Grant-in-Aid from The Ministry
of Health and Welfare of Japan (M.T., Y.K.).
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