118

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TEN PATIENTS WITH KABUKI MAKE-UP (NIIKAWA-KUROKI) SYNDROMEMiyako OGUNI'), Hiroshi MARUYAMAi)2), Hirokazu OGUNI'),

Kayoko SAITO'} and Yukio FUKUYAMA') i)Department of Pediatrics, Tokyo Women's Medical College

2)Matsudo Clinic

(Received June 22, 1993)

Introduction

The term Kabuki make-up syndrome was first

coined by Kuroki and Niikawa, working indepen-

dently, in 1981i}2). Subsequently, several cases

have been reported in Japan3)ny7) and several more

in other countries8}nyi2).

Characteristics of this syndrome include a

peculiar. facial appearance: eversion of the lower

lateral eyelid, arched eyebrows ･with the lateral

one third having sparse or dispersed hair, a

depressed nasal tip, and prominent ears. Skeletal

anomalies and dermatoglyphic abnormalities are

very comrnon, and mental retardation is present

in all cases.

The derMatoglyphic pattern described byNiikawa et al'3> in 1982 included an increased

digital ulnar loop and hypothenar loop patterns,

absence of the digital triradius c and/or d, and the

presence of fingertip pads.

We experienced 10 cases of this syndrome, four

of whom had also xeroderma pigmentosum. We

report here the clinical details of our 10 Kabuki

make-up syndrome cases.

Subjects

Ten patients with Kabuki make-up syndrome

were identified among the patients followed at

Matsudo Clinic (Table). Dermatoglyphic and

cytogenetic studies (Giemsa-trypsin banded pe-

ripheral lymphocyte chromosomes), and roent-

gengrams of the spinal column and hands were

obtained from all of these patients. Detailed in-

dividual past histories and family histories were

provided by their parents.

Results

In addition to the typical craniofacial anomalies

(Figure), case 1 had dermatoglyphic abnormalities,

short fifth fingers, hip dislocation, hearing loss,

obesity, epilepsy, and xeroderma pigmentosum.

Case 2 had short fifth fingers, cleft palate, obesity,

and a VSD, but no dermatoglyphic abnorm'alities.

Case 3 had dermatoglyphic abnormalities, stra-

bismus, short fifth fingers, a rib anbmaly, and

xeroderma pigmentosum. Case 4 had one dermato-

glyphic abnormality, strabismus, short fifth

fingers, and epilepsy. Case 5, who was 45,X had

one dermatoglyphic abnormality, strabismus,

short fifth fingers, epilepsy, and xeroderma pig-

mentosum. Case 6 had two dermatoglyphic ab-

normalities, .strabismus, cleft palate, hip disloca-

tion, blue sclerae, epilepsy and xeroderma pig-

mentosum, but no shortening of finger V. Case 7

had two dermatoglyphic abnormalities, strabis-

mus, short fifth fingers, ASD, VSD, epilepsy and

xeroderma pigmentosum. Case 8 had two der-

matoglyphic abnormalities, blue sclerae, and

epilepsy. Case 9 had dermatoglyphic abnormali-

ties, obesity, strabismus, and epilepsy, but no

shortening of finger V. Case 10 had one dermato-

glyphic abnormality, and epilepsy, but no shorten-

.ing of finger V. Cases 1 to 5 had definite lower

palpebral eversion, while cases 6 to 10 had only

mild eversion. Cases 9 and 10 had arched eye-

brows but the pattern of hair growth was es-

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Table　Ten　cases　of　Kabuki　make・up　syndrome

Case1 2 3 4 5 6 7 8 9 10

Manifestations

Sex F F M F F F M M F MAge（Years） 23 13 15 14 11 17 11 14 10 7

Mental　retardation severe severe mild moderate mlld severe severe severe moderate mild

Chromosome 46，XX 46，XX 46，XY 46，XX 45，X 46，XX 46，XY 46，XY 46，XX 46，XY

Craniofacial　anornalies

Lower　palpebra玉eversion 十 十 十 十 十 十 十 十 十 十

Arched　eyebrows　with　sparse十 十 十 十 十 十 十 十 十 十

1ateral　1／3

Prominent　ears 十 十 十 十 十 十 十 十 一 　

Depressed　nasa王tip 十 十 十 十 一 十 十 十 十 一

Ear　malfQrmatiGns 一 十 　 十 一 十 十 十 一 一

Abnormal　dentition 十 十 　十 十 十

一十 十 『

Spaced　teeth 十 　 十 十 十 十 十 十 ㎜ 　

High－arched　palate 十 一 一十 十 十 一 十 一 一

Epicanthus 十 一 十 十 十 十 十 十 十 十

Strabismus｝ 　 十 十． 十 十 十 ㎜ 十 一

Cleft　palate／lip一 十 』 一 一

十　 　 一 一

Preauricular　dimple 一 一 『 一 一 　 一 　 ｛ 『

Micrognathia『 一 　 一 一 一 』 一 一 一

Skeletal　abnormalities

Short丘nger（V） 十 十一

十 十 一 十 　 一 一

Short　middle　phalanx（V） 十 一 十 十 十 一 十 十 一 一

Scoliosis 十 『 十 　 一 十 十 一 一 一

Rib　anomaly 『 一 十 』 一 一 『 『 一 　

Hip　dislocation 十 一 　十

｝十

一 一 一 一

Foot　deformity 十 十 十 十 十 十 十 十 十 十

Short　stature 十 一 　十

一 十 十 一 一 『

Occasional　anomalies

Cardiovascular　anomaly 　 十 一 一 ｝ 『十 一 一 一

Blue　sclerae 十 『 『十

一 十 一十 一 一

Undescended　testis ｝ 一 一 一 一 』 一 一 一 一

Complications

Susceptibility　to　infection 十 十一 十 一 十 十 一 十 十

Recurrent　otitis　media 十 一 』十

一 『 『 一 　 ｝

Hearing　loss 十 一 『 　 　 一 一 一 一 一

Obesity 十 十｝ 　 一 　 一 一 一 ｝

Seizure 十 　 一 十 十 十 十 十 十 十

Xeroderma　pigmentosum 十 　 十 一 十 十 『 一 一 一

Dermatoglyphic丘ndings

Increased　ulnar　looPs 十 一 十 一 十 一 　 　 十 十

Absence　of　digital　triradius　c 一 一 十　 　 十 一 　 十 　

Absence　of　digital　triradius　d 十 　 十 十 一 『十 十 一 　

Increased　hypothenar　loops 十 一 『 一 　 十 十 十 十 一

Presence　of　fingertip　pads 十 十 十 十 十 十 十 十 十 十

sentially　norma1．

　Of　the　10　patients，　six　were　female　and　four

were　male。　Their　ages　at　the　time　of　study　ranged

from　7　to　23　years　with　a　mean　of　14　years．　The

prenatal　an～l　perinatal　histories　of　these　patients

were　non　contributory．　Weight，　height．and　head

circumference　values　at　birth　were　all　with孟n

normal　range．　In　the　postnatal　per量od，　six　patients

had　experienced　difficulty　in　feeding　which　lead　to

failure　to　thrive　and　delayed　development．　S三x

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120

1 2 3 4 5

6 7

Figure

8 9

Ten patients of Kabuki make-up syndrome: Facial appearance

10

er . .. `'W

patients (60%) had short stature, in the -2.3 SD to

-5.1 SD range. Heights of the remaining 4 pa-

tients (40%) were within normal range. All 10

patients were mentally retarded: 5 severely, 2

moderately and, the remaining 3 mildly.

All had the characteristic peculiar face; lower

palpebral eversion and arched eyebrows, foot de-

formities and dermatoglyphic abnormalities with

fingertip pads. Seven of these patients had a short

nasal septum, prominent ears, depressed nasal

tip, abnormal dentition, spaced teeth, epicanthus

and susceptibility to infection. Six had strabismus

and a short middle fifth phalanx bilaterally, and

five had a high arched palate, scoliosis and short

fifth fingers. Cleft palate was present in 3 cases,

congenital cardiac anomalies in two: one had ASD

and PDA, and the other had VSD and a ribanomaly (11 ribs).

Noteworthy complications included epilepsy

(8 cases) and xeroderma pigmentosum (4 cases).

Among the 8 cases with epilepsy, 3 had gener-

alized tonic clonic seizure (GTCS), 3 had gener-

alized tonic seizure (GTS), 2 had complex partial

seizure (CPS), and 1 had simple partial seizure

(SPS). One had both GTCS and CPS. In three of

these cases, seizure control was difficult.

Giemsa-trypsin (G) was used to analyze periph-

eral lymphocyte chromosomes of all patients and

the only anomaly found was in the 45,X patient.

There was consanguinity on the paternal side in

one case. As to family history, three cases had

neurological disorders within the family: autism,

epilepsy and hydrocephalus in one family each.

None had a family history of Kabuki make-up

syndrome.

Discussion

Our 10 patients all had a peculiar facial appear-

ance with skeletal and dermatoglyphic anomalies,

compatible with Kabuki make-up syndrome, as

reported by Kuroki and Niikawa. Unlike Kuroki

and Niikawa's cases, half of our patients had

severe mental retardation. In addition the com- 'plications of epilepsy and xeroderma pigmento-

sum were rnore prevalent in our cases.

Types of seizures, seizure onset, EEG findings

and response to treatment were variable.

Four of our 10 patients had xeroderma pig-

mentosum, an exceptional complication in this

disease. The unusual combination of Kabuki

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121

make-up syndrome and this dermatologic disorder

has not previously been reported, to our knowl-

edge. Xeroderma pigmentosum is an autosomal

recessive disease characterized by cutaneous

photosensitivity, a decreased ability to repair

deoxyribonucleic acid (DNA) damaged by ultra-

violet radiationi`). Children with xeroderma pig-

mentosum develop erythema, freckling, and in-

creased pigmentation after exposure to sunlight.

The onset of most cases is in early childhood.

Genetic analysis of cultured cells from xeroderma

pigmentosum patients has revealed the presence

of 8 complementation groups, all showing a de-

ficiency in the excision of UV-induced lesions in

the DNA. Excision repair cross complementing

<ERCC) chrornosomal loci -1, 2, 3, 4, 5 and6 have

been identifiedi5)Ni7).

Although Kabuki make-up syndrome seems to

be congenital, the association of other major

anomalies was variable and no common origin

could be identified. Congenital heart disease, cleft

palate, and other abnormalities can be induced in

early pregnancy, while minor facial anomalies

may develop in later pregnancy. In addition to

these findings, abnormal dermatoglyphics, scolio-

sis and short stature, which became more promi-

nent over time, were evident. There were no

familial cases among our patients. There has been

only one case report describing familial occurrence

of Kabuki make-up syndrome, in two siblings and

their father8). As Niikawa et al suggested3), Kabuki

make-up syndrome may be an autosomal domi-

nant disorder in which the majority of patients

have a new mutation, because virtually all pa-

tients encountered to date have been sporadic and

only one had known affected family members.

Several institutions have reported patients with

Kabuki make-up syndrome accompanying sexchromosomal abnormalities, such as 45,X6)7). We

also found one case with a ring X chromosome

(45,X). In addition, we have four cases of xero-

derma pigmentosum with this syndrome. These

facts may offer clues as to the role of chromosomal

anomalies in Kabuki make-up syndrome. As yet,

however, results are inconclusive.

Further clinical and molecular studies are

necessary to elucidate the cause of this syndrome.

References

1) Kuroki Y, Suzuki Y, Chyo H et al; A new rnalforma-

tion syndrome of long palpebral fissures, large ears,

depressed nasal tip, and skeletal anomalies associated

with postnatal dwarfism and mental retardation. J

Pediatr 99: 570-573, 1981

2) Niikawa N, Matsuura N, Fukushima Y et al: Kabuki make-up syndrome: A syndrome of mental retardation, unusual facies, lar:ge and protruding ears,

and postnatal growth deficiency.J Pediatr 99: 565-569,

19813) 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

4) Iwama Y, Sugiyama S, Kaiga K et al: Kabuki make-

up syndrome associated with megaureter. Acta Paediatr

Jpn 29: 182-185, l987

5) Kaneko H, Suma K, Takeuchi Y et al: An operative

case of Kabuki make-up syndrome with ASD and pulmonary hypertension. Jpn J Thorac Surg 38: 737-

740, 1985

6) Ishii M, Ebihara Y, Yamakawa T et al: One case of

Kabuki make-up syndrome with Turner syndrome. J Jpn Pediatr Soc 96: 1135, 1992

7) Kajii M, Daidou S, Okuno A et al: Five cases of Kabuki make-up syndrome with Turner syndrome. Program and Abstracts in the 36th Congress of Society

of Japanese Human Genetics: 117, 1994

8) Halal F, Gledhill R, Dudkiewicz A: Autosomal dominant inheritance of the Kabuki make-up (Niikawa-

Kuroki) syndrome. AmJ Med Genet 33: 376-381, 1989

9) Gillis R, Klar A, Gross-Kieselstein E: The Niikawa-Kuroki (Kabuki make-up) syndrome in a Moslem Ar･ab child. Clin Genet 38: 378-381, 1990

10) Kaiser-Kupfer MI, Mulvihill JJ, Klein KL et al:

The Niikawa-Kuroki (Kabuki make-up) syndrome in an

American Black. AmJ Ophthal 102: 667-668, 1986

Il) Koutras A, Fisher S: Niikawa-Kuroki syndrome: A new malformation syndrome of positnatal dwarfism,

mental retardation, unusual face and protruding ears.J

Pediatr 101: 417-419, 1982

12) Braun OH, Schmid E: Kabuki make-up syndrome (Niikawa-Kuroki syndrome) in Europe.J Pediatr 105:

849-850, 1984

13) Niikawa N, Kuroki Y, Kajii T: The dermatqglyphic

pattern of the Kabuki make-up syndrome. Clin Genet

21: 315-320, 1982

14) Patton LL, Valdez IH: Xeroderma pigmentosum: Review and report of a case. Oral Surg Oral Med Oral

Pathol 71: 297-300, I991

15) Bootsma D: The genetic basis of xeroderma pigmento-

sum. Ann Genet 34: 143-I50, 1991

16) Tanaka K, Miura N, Satokata I: Analysis of a huTpan DNA excision repair gene involved in group A

xeroderma pigmentosum-and containing a zinc-finger

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122

　domain．　Nature　348：73－76，1990

17）Weeda　G，　Wiegant　J，　Van　Der　Ploeg　M：L㏄aliz研

　tion　of　the　xeroderma　pigmentosum　group　B－correcting

gene　ERCC3　to　human　chromosome　2q　21．　Genomics

10：1035－1040，1991

歌舞伎メーキャップ症候群の10例

　1凍京女子医科大学　小児科，2）松戸クリニック

オグニミ　ヤ　コ　　　マルヤマ　　ヒロシ　　　　オグニ　　ヒロカズ

小国美也子1）・丸山　　博1）2）・小国　弘量1）

サイトウカ　ヨ　コ　　　フクヤマ　　ユキォ

斎藤加代子1）・福山　幸夫1）

　歌舞伎メーキャップ症候群は，1981年黒木らおよび新川らによって初めて記載された．我々は，10

例の歌舞伎メーキャップ症候群を経験したので報告する．7歳から23歳までの女6例，男4例である．

10例とも切れ長眼裂，下眼裂の外反，外側1／2の粗な弓状眉毛という特徴的顔貌を呈しており，手掌紋

もこの症候群に一致していた．この10例中8例にてんかんを合併し，6例は乳児期より成長発達の遅

れがあり低身長を呈していた．4例に色素性乾皮症，3例に口蓋裂，2例に心奇形を合併していた．

また1例は染色体が，45，Xであった．色素性乾皮症は8つの相補群に分かれ，クロマチン制御因子

が欠けているため，除去修復できないと考えられている．除去関連因子クロマチン因子の遺伝子座は

かなり解明されている．歌舞伎メーキャップ症候群とターナー症候群との合併は，注目されているが，

色素性乾皮症と歌舞伎メーキャップ症候群との関連性も，今後，歌舞伎メーキャップ症候群の遺伝子

工学的研究の鍵となるかもしれない．

一E122一