ito (incontinentia pigmenti achromians)
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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
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