A Malformation Complex of

Ectrodactyly, Clefting and Hypomelanosis of

Ito (Incontinentia Pigmenti Achromians)

RAY E. STEWART, D.M.D., M.S.

STEVEN FUNDERBURK, M.D.

YOSHIO SETOGUCHI, M.D.Torrance, California 90509

A case is described which, at birth, had a bizarre pattern of Aypopigmentation (incontinentiapigment achromians), ectrodactyly involving all four extremities, and unilateral cleft lip andpalate.

This patient does not have the seizures or other neurological and developmentalanomalies previously described as associated with Aypopigmentation of Ito. This condition isalso clearly different from the syndrome of ectrodactyly, ectodermal dysplasia, andclefting (EEC).

We have recently observed four-month-old

Mexican-American female infant with an in-

teresting constellation of anomalies, including

_ unilateral complete clefts of the lip and pal-

ate, ectrodactyly of the hands and feet, and

generalized abnormalities in skin pigmenta-

tion. The association of ectodermal changes,

ectrodactyly, and oralfacial clefting has been

well documented in the EEC syndrome (ec-

trodactyly, ectodermal dysplasia, and clefting

syndrome). However, this patient clearly does

not fall into this classification.

Clinical findings

The child was the product of a full-term,

uncomplicated pregnancy of a 33-year-old

gravida-4, para-4, abortion-0, mother and a

34-year-old father. The older siblings are nor-

mal. There is no family history of congenital

malformations, and there is no history of con-

sanguinity. There was no known exposure to

radiation, drugs, or other teratogens at the

time of conception or during the pregnancy.

However, the mother hadgallstone surgery

preceded by multiple diagnostic. x-rays oneyear prior to the pregnancy. _

Birth weight was 8 lbs., 11 oz. The infantwas vigorous and alert and had good muscle

Dr. Stewart is affiliated with UCLA/Harbor GeneralHospital, Torrance, California.

Drs. Funderburk and Setoguchi are affiliated W1th the

Departments of Pediatrics and Psychiatry UCLA School

of Medicine, Los Angeles.

tone. The child has developed normally,

reaching all ofher age-appropriate milestones

with no evidence of neurological or other

problems. The Denver Developmental Scales

yielded an intelligence quotient of 100 at 14

months of age.

Examination of the head and neck revealed

unilateral complete cleft of the lip and palate.

There was mild hypoplasia of the right exter-

nal ear (Figure 1).

Examination of the skin revealed a peculiar

generalized pattern of hypopigmentation over

the entire body, including the head, neck, and

face. On the dorsum, the pigmentation as-

sumed a swirling pattern. There was midline

demarcation of the pigment distribution an-

teriorly, and there was a linear distribution

on the arms and legs. Several of the hypopig-

mented areas were mildly desquamative. Bi-

opsy of these areas showed no histopatholog-

ical changes. There was a pink discoloration

in the hypopigmented patches of skin over the

left shoulder, on both buttocks, and in both

axillae. There were several small heman-

glomas located in the midback and glutialreglons The affected areas of skin were nor-mal in texture. Sensation was intact, andsweating was normal.The hair and nails were of normal quality

and quantity. The eyes were normal and with-out obstruction or defects of the lacrimalducts. There were "lobster-claw'" deformitiesof both hands and absence of the third digitbilaterally. There was a bifid thumb on the

358

Stewart, et al., ECTRODACTYLY, CLEFTING AND HYPOMELANOSIS

FIGURE 1. Patient at age 8 weeks showing unilat-eral complete cleft of lip and palate, hypopigmentationon trunk, arms and face, and ectrodactyly.

right, and a rudimentary accessory index fin-

ger on the left. In addition, there was wide

spacing between the second and third toes on

the right foot and between the third and

fourth toes on the left foot. Syndactyly was

present between the third and fourth toes on

the right side and between the second and

third toes on the left side (Figure 2). In addi-

tion, there were deep horizontal plantar

grooves in the first interdigital spaces bilat-

erally.

The remainder of the physical examination

was unremarkable.

Trypsin-Giemsa banded chromosome anal-

ysis done on peripheral blood lymphocytes

was normal.

Radiographic findings

Anterior posterior radiographs were done

of the hands and feet. The right hand ex-

hibited an absence of the third ray and ossi-

fication of the middle phalanx of the fifth

digit. There was clinodactyly of the second

and fifth rays and nonossification of the distal

phalanx of the second ray. Three phalanges

were noted in the thumb. There was no evi-

dence of bony fusion. (See Figure 3.)

The left hand exhibited an absence of the

359

phalanges of the third ray and clinodactyly

of the first and fifth rays with no evidence of

bony fusion.

The left foot showed syndactyly of the pha-

langes of the third and fourth toes with an

absence of ossification of the middle phalanx

of the fourth toe. Clinodactyly of the fifth toe

was noted with absence of ossification of the

distal and middle phalanges of the fifth toe.

There was no evidence of bony fusion (Figure

4).

The right foot had supernumerary rays be-

tween the second and third digits with syn-

dactyly of toes two, three, and four. There

was shortening of the third metatarsal and a

lack of ossification of the middle phalanx of

the fifth toe. Again, there was no evidence of

bony fusion.

Discussion

The clinical findings described in this pa-

tient closely resemble a condition described

by Ito (1952) which has been variously termed

incontinentia pigmenti achromians, systema-

tized achromic nevus (Coupe, 1975; Cram,

1974) and hypomelanosis of Ito (Jelinek,

1973). In its classic description, this condition

is said to consist of macular hypopigmented

whorls, streaks, and patches in a bilateral or

unilateral distribution affecting almost any

portion of the body surface. Because of the

differences in the natural history of the cuta-

neous defect, the histologic features, and the

pattern of inheritance, this condition has been

regarded as distinct and separate from incon-

FIGURE 2. Feet showing 3-4 syndactyly on rightand 2-3 syndactyly on left. Hypopigmentation is alsoapparent.

360

Cleft Palate Journal, October 1979, Vol. 16 No. 4

FIGURE 3. Radiographs of hands.

tinentia pigmenti which it resembles but as a

negative image (Jelinek, et al., 1973).

Patients with the condition as described by

Ito (1952) either have skin lesions at birth or

develop lesions early in life without a preced-

ing bullous or verrucous stage. The lesions are

diagnostic clinically because of the extensive

areas of bizarre, whorled, marbled, and

streaked hypopigmentation which appear to

be unique to this disorder. Unfortunately,

there are no specific histologic changes. Var-

ious reports on sections from hypopigmented

lesions show only decreased numbers of mel-

anocytes, reduction of pigment production in

DOPA preparations, and incomplete melani-

zation of melanosomes on electron microscopy

(Stoebner, 1970). Compared to normally pig-

mented skin, melanosomes in keratinocytes

from hypopigmented areas are fewer in num-

ber and are packaged individually (Cram,

1974).

Reports of this condition in more than 30

affected individuals of various ethnic origins

reveal that it is accompanied by associated

abnormalities of varying structures and sever-

ity in 50% of the cases. Central nervous system

dysfunction, particularly seizure disorders

and delayed development, have been the most

consequential of these defects, but ocular and

musculoskeletal anomalies also have occurred

with significant frequency.

In a report of eight patients by Schwartz et

al. (1977), there was a particularly high inci-

dence of nonspecific abnormalities. Six of the

eight patients had sufficient developmental

delay to warrant placement in special educa-

tion classes. Four patients had seizure disor-

ders of varying degrees of severity. In three,

onset of seizures occurred prior to the third

year of life. All four patients with seizures had

significant scoliosis, and in three, prominent

asymmetry of the lower limbs was noted.

Three of the eight patients had ophthalmo-

logic abnormalities, which included isolated

iridal heterochromia, a mild alternating eso-

tropia and myopia, microphthalmia, hyper-

telorism, and nystagmus. Strabismus has been

frequently reported along with other anoma-

lies, most significantly corneal opacity and

choroidal atrophy (Jelinek, 1973).

Abnormalities of teeth, hair, and nails have

been reported in incontinentia pigmenti ach-

romians, but these are apparently not present

in the majority of cases.

Stewart, et al., ECTRODACTYLY, CLEFTING AND HYPOMELANOSIS

It is essential to differentiate and distin-

guish incontinentia pigmenti achromian from

incontinentia pigmenti (Bloch-Sulzberger)

with which it is frequently compared and

often confused. Although similarities do exist

between the two conditions, there are several

important differences.

Incontinentia pigmenti is an X-linked dom-

inant trait which is observed most frequently

in females. The condition is thought to be

lethal for most affected males (Gordon, 1970).

The paucity of affected males and the in-

creased incidence of spontaneous abortions in

women who carry the IP gene support this

hypothesis. The cutaneous manifestations

usually consist of an erythematous and bul-

lous phase in infancy, followed by a verruc-

cous phase of variable duration. Pigmented

lesions are rarely present at birth but fre-

quently develop during infancy and early

childhood. The distinctive histologic feature

of pigment-laden macrophages in the dermis

(pigmentary incontinence) gives the disease

its name (Morgan, 1971). Hypopigmented

lesions are unusual, and have never been de-

361

scribed in the absence of the more classic

hyperpigmented lesions. Associated anomalies

are frequent, most commonly involving the

central nervous system, eyes, musculoskeletal

system, hair, and teeth.

Pathogenesis

The role of genetics in the pathogenesis of

hypopigmentation of Ito is not clear (Ito,

1952). The majority of reported cases are

sporadic. However, a few instances of familial

occurrence have been reported. Grosshans et

al. (1971) reported an affected mother with

three affected daughters. Jelinek et al. (1973)

noted a possible occurrence in a distant rela-

tive of one of his patients.

Cram and Fukuyama (1974) reported on a

boy with hypopigmentation and seizures. His

mother and maternal grandfather were said

to have limited areas of hypopigmentation.

Rubin (1972) described an affected girl whose

two brothers had macular hypopigmentation

and whose father and paternal uncle were

also said to have had an extensive pigmentary

disorder.

FIGURE 4. Radiographs of feet.

362 Cleft Palate Journal, October 1979, Vol. 16 No. 4

The preponderance of females affected with

this disorder (4:1) raises a question of a sex-

linked phenomenon. However, this remains

speculative.

The consistency of multiple malformations

involving skin, musculoskeletal, ocular, and

central nervous system structures suggests that

this entity should be classified as a malfor-

mation complex.

A possible explanation of the pathogenesis

of the observed malformations lies in a gen-

eralized defect in neural crest cell differentia-

tion, migration, or cellular interaction. All of

the structural malformations which were ob-

served in our patient and those described in

the literature could arise secondary to a defect

in neural crest cell activity. The pigmentation

anomalies could be attributed to an abnormal

distribution of melanocytes early in develop-

ment. The limb malformations and facial

clefting could be explained by a disruption in

the interaction between neural crest cells and

the underlying mesenchymal precursors of the

affected structures (e.g., faulty ectodermal-

mesodermal interaction). Certainly the re-

ported defects in CNS development and ocu-

lar abnormalities could arise from similar

mechanisms. It is interesting and significant

to note that malformations similar to those

observed in this group of patients have been

experimentally produced, either singly or as

clusters, in various animal models by manip-

ulating or interfering with normal neural crest

cell development (Johnson, 1975).

_- Hypopigmentation as a discrete entity oc-

curs infrequently in infants and children

(Hurwitz, 1970). When the phenomenon is

observed with no previous history of inflam-

matory processes, it should be regarded as a

harbinger of additional associated problems

demanding further investigation and exami-

nation, meludmg developmental testing, andcareful inspection for musculoskeletal, ocular,

_ and clefting abnormalities. If scoliosis or llmbasymmetry is present, an electroencephalo-gram and neurologic assessment are indicatedsince the likelihood of seizures with this com-bination of defects is high (Schwartz, 1977).

Summary and conclusions

A four-month-old infant is presented Atbirth, she had an unusual array of anomaliesmeludlng cleftlip andcleft palate, limb ab-normalities, and a bizarre pattern ofhypopig-mentation. Unlike many reported cases, this

patient had no detectable developmental ab-normalities or seizure problems on follow-upexamination at fourteen months of age. Theclinical findings are consistent with a diag-nosis of hypomelanosis of Ito (incontinentiapigmenti achromians), which appears to be ahighly variable disorder of uncertain etiology.The consistent involvement of structures andtissues directly related to neural crest cellfunction suggests that this disorder could rea-sonably be classified as a malformation complex.The nature of genetic influence in this con-

dition is unclear, and like the problem ofaccurate determination of a prognosis for af-fected individuals, the precise etiology awaitsfurther investigation.

Reprints: Ray E. Stewart, D.M. D.UCLA/Harbor Hospital

Building E-4Torrance, CA. 90509

References

CoupPE, R., Unilateral systematized achromic nevus, Der-matologica, 134, 19, 1967.

Coupr, R., Hypochromic nevus: The inheritance ques-tion, Arch. Dermatol., 111, 394, 1975.

Cram, D. L. and FuKuyamMa, K., Proceedings: Unilateralsystematized hypochromic nevus, Arck. Dermatol., 109,416, 1974.

Gorpon, H. and Gorpon, W., Incontinentia pigmenti.Clinical and genetical studles of two familial cases,Dermatologica, 140, 150, 1970.

GrossHans, E. M., StormnEr, P., Bercornp, H., Incon-tinentia pigmenti achromians (Ito): Etude clinique ethistopathologique, Dermatologica, 142, 65, 1971.

Hamapa, T., Saro, T., Suca1, T. and Morita, Y., Incon-tinentia pigmenti achromians (Ito), Arck. Dermatol., 96,673, 1967.

Hurwitz, S. and Braverman, J. M., White spots intuberous sclerosis, J. Pediatr., 77, 587, 1970.

Iro, M., Studies of melanin XI. Incontinentia pigmentiachromians, a singular case of nevus depigmentosussystematicus bilateralis, TohokuJ. Exp. Med., 55 (Suppl.),57, 1952.

JEuingek, J. C., Bart, R. $. and ScHirr, G. M., Hypome-lanosis of Ito ("incontinentia pigmenti achromlans5,

Arch. Dermatol., 107, 596, 1973.

Jounson, M. C. and Pratt, R. M., The neural crest in

normal and abnormal craniofacial development. In

Extracellular matrix influences on gene expression.

New York: Academic Press, Inc., 1975.

Morcan, J. D., Incontinentia pigmenti (Bloch-Sulzber-

ger syndrome), Am. J. Dis. Child., 122, 294, 1971.

Rusin, M. B., Incontinentia pigmenti achromians. Mul-

tiple cases within a family, Arch. Dermatol., 105, 424,

1972.ScHwARTZz, M. F., Hypomelanosis of Ito (incontinentia

pigmenti achromians): A neurocutaneous syndrome,/.

- Pediatr., 90, 236-240, 1977.

StoEBNER, P. andGrossHans, E. M., Incontinentia pig-

menti achromlans (Ito). Etude ultrastrueturale Arch.

Klin. Exp. Derm., 239, 227, 1970.