Pediatric Dermatology Vol. 20 No. 6 491–494, 2003

Incontinentia Pigmenti Associated with
Cerebral Palsy and Cerebral Leukomalacia:
A Case Report and Literature Review
Syed N. Shah, M.R.C.P.,* Sam Gibbs, M.R.C.P.,§ Chris J. Upton, M.R.C.P.,
Fred E. Pickworth, F.R.C.R.,à and Jennifer J. Garioch, F.R.C.P.*
Department of *Dermatology, Paediatrics, and àRadiology, Norfolk and Norwich University Hospital, Norwich,
United Kingdom, and §Department of Dermatology, Addenbrookes Hospital, Cambridge, United Kingdom

Abstract: Incontinentia pigmenti (IP) is a multisystem disorder with
characteristic cutaneous signs. After the skin, the central nervous system is
the next most affected system. We report a child with IP and left-sided
hemiparesis and cerebral periventricular leukomalacia on magnetic resonance imaging (MRI). The MRI findings would support ischemia sustained
perinatally.

Incontinentia pigmenti (IP) was first described by
Garrod in 1906 (1). It was further defined by Bardach in
1925 (2) and by Bloch in 1926 (3). It is a multisystem
disorder that is inherited in an X-linked dominant fashion with lethality in males. The skin features are diagnostic and classically occur in four stages, although not
all stages may be observed:

system (mental deficiency, microcephaly, spasticity, seizures, and magnetic resonance imaging [MRI] change).
Ischemia of the peripheral retinal field has also been
described (7).

• Stage 1: Erythema, vesicles, and bullae typically
configured in a linear pattern.
• Stage 2: Papules, verrucous lesions, and hyperkeratosis.
• Stage 3: Hyperpigmentation.
• Stage 4: Hypopigmentation and atrophy of the skin.

A full-term infant girl was born by uncomplicated vaginal delivery as the first child of unrelated parents. On day
4 she developed focal seizures which rapidly generalized.
They resolved after 12 hours with no sequelae. A cranial
ultrasound performed at the time was normal. At 6 weeks
of age she presented with a 4-week history of a blistering
eruption, which had started on her hands and then
spread to her limbs. Examination revealed bullae arranged in a linear pattern on the hands and fingers and
overlying the Achilles tendon (Fig. 1). A clinical diagnosis of IP was suspected and confirmed by skin biopsy
(Fig. 2).
By the age of 4 months, her blisters were replaced by
keratotic and verruciform lesions (Fig. 3). The growth

Other systems that may be involved include the teeth
(hypodontia, microdontia, dysplasia, and delayed eruption) (3–6); the musculoskeletal system (hemivertebrae,
kyphoscoliosis, extra rib, syndactyly, hemiatrophy, and
short arms and legs); the eyes (strabismus, retinal dysplasia, retinal detachment, uveitis, keratitis, cataract,
retrolental dysplasia, blue sclerae, and pigment retinopathy); the hair (alopecia); and the central nervous

CASE REPORT

Address correspondence to S. N. Shah, M.R.C.P., Department
of Dermatology, Norfolk and Norwich University Hospital, Colney Road, Norwich, UK, NR4 7UZ.

491

492 Pediatric Dermatology Vol. 20 No. 6 November/December 2003

Figure 1. Hand and fingers at 6 weeks of age show hyperkeratosis and bullae arranged in a linear pattern.

Figure 2. Intraepidermal bulla set in an acanthotic and
dyskeratotic epidermis. (Hematoxylin-eosin; magnification
250·.)

Figure 3. Hand at 4 months of age with a hyperkeratotic and
verruciform lesion.

and development of the infant were well within normal
limits. However, at 6 months of age the parents noticed
that she did not appear to be using her left arm and leg.

Figure 4. Perineumat 1 year of age showing classical splashed and whorled macular pigmentation.

Figure 5. MRI scan at 14 months of age. (A) T2-weighted
axial image shows high signal areas in the periventricular
white matter due to gliosis. (B) Coronal image shows dilated
lateral ventricles secondary to loss of volume of the adjacent
white matter. Note the close proximity of the cortical gray
matter to the ventricular margins. These changes are more
marked on the right side.

Examination revealed increased tone and reflexes on the
left together with left sensory inattention.
At the age of 1 year she had developed linear hyperpigmentation on her right shin and left calf. In addition,
she had splashed and whorled macular pigmented areas,
characteristic of IP, on the perineum and abdomen (Fig.
4). Her neurologic signs did not progress significantly;
she continued to have a mild left hemiparesis. Delayed
eruption of the teeth was noted, with only one incisor
evident at the age of 1 year. No ophthalmologic abnormalities were detected. MRI scan of her brain performed
at 14 months of age showed changes typical of end-stage
periventricular leukomalacia (Fig. 5). The changes were
more marked on the right side, in keeping with the
neurologic signs. At the age 18 months she was walking
and starting to talk. Her left hemiparesis has remained
mild and has not progressed. She has kept up with her
main developmental milestones.

Shah et al: Incontinentia Pigmenti with CNS Involvement

Examination of her mother found no evidence of IP.
Genetic analysis using blood from our patient revealed a
deletion mutation at the NEMO gene, but this mutation
was negative in the mother’s blood. It confirmed our
clinical impression of a new mutation.
DISCUSSION
Incontinentia pigmenti is a familial, X-linked, neurocutaneous syndrome. Mutations in the NEMO gene, which
encodes a critical component of the neurofibromatosis
kappa-B (NF-jB) pathway, were found to be responsible
for IP (8,9). Most cases of IP are due to a recurrent
deletion within NEMO that removes exons 4–10 (8–10).
The male hemizygous state usually results in early fetal
loss, and the vast majority of cases are female (male:
female ratio of 1:37) (4). Surviving male patients are
described in the literature. A number of reported male
cases have an XXY karyotype, however, Aradhya et al
(8) recently showed that males could also have IP caused
by duplication mutations of a cytosine tract in exon 10 of
NEMO.
Neurologic involvement occurs in approximately onethird of cases. Seizures, global developmental delay, and
spastic paresis are the most common manifestations of
neurologic involvement (11) and may occur very early in
the disease. Using MRI, Yoshikawa et al (12) detected a
cavity in the brain of a 1-month-old infant girl with IP.
It was nonprogressive and the pathophysiology was
poorly understood. A number of studies of histopathologic and neuroradiologic observations have speculated
that vascular anomalies causing ischemia or an abnormal
protein triggering an encephalitic process may be
responsible for the neurologic complications of IP.
Pauscal-Castroviejo et al (13) described brain changes
noted on MRI in four girls with IP; there were hyperintensities on T1- and T2-weighted images that extended
through the cortical and subcortical zones. The changes
were bilateral in two patients and unilateral in the other
two. Associated white matter anomalies were seen in
both cerebral hemispheres in three of the four girls. The
most severe lesions were mainly in the subcortical white
matter. These were diffuse and homogeneous, involving
the cortex, ependymal, and subependymal zones. There
was also associated cerebral hemiatrophy and hypoplasia of the corpus callosum with cerebellar hemiatrophy in
two of them.
Similar lesions were demonstrated as low densities by
computed tomography (CT) scan and hyperintensities
by MRI in other studies of IP (14–16). There was good
correlation between the MRI changes, neuronal dysplasia, and neuronal loss on histologic observation
(13,14). The authors suggested that the changes on MRI

493

coincided well with an infection/vaccinal process that led
to encephalitis with variable expression and encephaloclastic effect on the central nervous system (CNS)
(15–17).
In an MRI brain study of two sisters with IP, Aydigoz
and Midia (18) found hypoplasia of the corpus callosum,
enlargement of the lateral ventricles, and periventricular white matter. They also found microphthalmia and retinal detachment. They postulated that
these changes could represent cerebral and retinal
ischemia arising from a periventricular inflammatory
infiltrate in the cerebral hemisphere and retinal arteriolar system.
Lee et al (19) did a prospective case study of seven
patients with IP using MRI, magnetic resonance (MR)
angiography, and multislice proton MR spectroscopic
imaging. Five of the patients had abnormal MRI changes in the form of increased T2 signals, ventricular
enlargement, white matter infarcts, cerebral atrophy,
hemorrhages and ischemia, and evidence of cerebral
infarction. In three severely affected patients there were
similarities to periventricular leukomalacia, a condition
of premature infants in which a global hypoxic insult
leads to infarction of the vascular watershed regions in
the periventricular white matter. There was an association between CNS ischemic changes and retinal vascular occlusive disease. MR angiographic studies were
abnormal in two patients. One had a carotid aneurysm,
which could have resulted from neonatal damage of the
involved vessels. In the other patient, branches of the left
cerebral artery could not be visualized, possibly due to
reduced blood flow in a hemisphere with reduced cortical
volumes. Four of five patients undergoing spectroscopic
imaging showed reduced N-acetyl aspartate, which has
been shown to be a neuronal marker, reflecting a neuronal loss, and increased lactate levels, signifying chronic
ischemia. They concluded that at least some of the CNS
abnormalities were the result of vascular occlusive events
and resultant ischemia similar to that seen in the retina.
Other studies suggested the same kind of ischemic
changes for the retina (20–22).
Kasai et al (23) reported a case of cerebral infarction
in multiple arterial regions of the brain in IP, evaluated
with single-photon emission computed tomography
(SPECT), which was also able to detect sluggish blood
flow in the brain. They recommended IP should be
included among the neurocutaneous syndromes associated with ischemic strokes and advocated the use of
aspirin as prophylaxis.
In summary, we report a patient with IP who
had neurologic signs and changes on MRI. MRI features were highly suggestive of global ischemia during
intrauterine life and are entirely consistent with the

494 Pediatric Dermatology Vol. 20 No. 6 November/December 2003

nonprogressive neurologic deficit observed clinically. In
addition, we reviewed the current literature, which would
suggest a relationship between vascular insult and the
neurologic findings in IP.
ACKNOWLEDGMENT
We would like to thank Dr. Dorothy Trump, Consultant
Geneticist at Addenbrookes Hospital, Cambridge, UK,
for performing the genetic tests.
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