Transcript INCONTINENTIA PIGMENTI - Abdel Hamid Derm Atlas

Incontinentia pigmenti
A Nonsense Mutation in the IKBKG Gene in Mares with Incontinenta pigmenti
CUTANEOUS MANIFESTATIONS
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Cutaneous findings are indicative of the disease and usually appear following a chronological sequence,
characterized by a progression through four distinct stages, although some of them may temporarily overlap or not
even develop in some patients.
Stage 1, known as inflammatory or vesicular stage, is characterized by the development of papules, vesicles and
pustules on an erythematous base, distributed linearly along the lines of Blaschko . These vesicles may vary in
size from 1 mm to 1 cm or more and pustules may also occur. This phase can be confused with herpes simplex or
impetigo. Lesions are mainly seen on the extremities, but may also occur on the trunk, head and neck. The
vesicular stage occurs in 90-95% of patients. In most patients (> 90%) lesions are present at birth or develop
during the first two weeks of life and then disappear by 4 months of age. In some cases, they may appear after the
first year of life or still during the intrauterine period. Self-limited episodes of recurrent vesicular lesions are
observed even in older children, in association with an acute febrile illness.
Stage 2, also known as verrucous stage, is characterized by plaques and warty papules linearly arranged over an
erythematous base, also following the lines of Blaschko . In general, the lesions develop on the extremities and
trunk, but can also be seen on the head and neck. Its location may or may not correspond to the previous
distribution of inflammation during stage 1. The occurrence of warty lesions is reported in 70% of cases. In most
patients, they develop within two to six weeks and usually disappear by six months of age .Occasionally, warty
lesions persist into adulthood or appear later during the disease process, in the form of linear verrucous striae with
a predilection for palms and soles
Stage 3 or hyperpigmented stage is defined by the development of linear or whorled lesions, with a brownish
pigmentation, which may be accompanied by atrophy . This stage occurs in 90-98% of patients with IP. The most
common distribution of these lesions involves the trunk and extremities, but they may also be present in the skin
folds on the head and neck areas. Nipples, axillae and groin can also be frequently affected by hyperpigmentation.
The location of these lesions does not always correlate with areas of prior cutaneous involvement during earlier
stages. This suggests that hyperpigmentation could be independent of the inflammatory process. These lesions
usually develop during the first months of life and slowly disappear during adolescence. However, areas of
hyperpigmentation may persist in some patients until about forty years of age, especially in the axillae and groin
Stage 4, known as atrophic or hypopigmented, is characterized by areas of hypopigmentation, atrophy and
absence of hair, most frequently observed on the lower extremities . These lesions usually develop during
adolescence, persist into adulthood and may be permanent. They are observed in 30% to 75% of patients with IP.
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INCONTINENTIA
PIGMENTI: One of the
ways IP can affect
adults.
Vesicular stage of incontinentia pigmenti
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Stage 1: Vesicular
Most often affects
extremities and scalp but
can arise on any part of
body
Red, blister-like lesions
Often appear grouped in
lines along the arms and
legs (following socalled lines of Blaschko)
Present at birth or within
the first 2 weeks of life in
90% of patients
May last from a few weeks
to a few months and recur
throughout the first few
months of life
Incontinentia pigmenti
Incontinentia pigmenti
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Incontinentia pigmenti, also known as BlochSulzberger syndrome, is an uncommon sex-linked
inherited syndrome reported primarily in females, as
it is often lethal to male fetuses in utero. Most often
diagnosed during infancy because of the striking
cutaneous findings that typical followBlaschko lines.
During childhood persistent abnormalities of other
systems (ocular, dental, skeletal, and CNS) occur,
leading to blindness, neurological problems, and
disabling functional deficits.
Cutaneous lesions generally progress through four
stages that may show some overlap, during infancy
and early childhood. However, one or more of the
stages may be unapparent. The vesicular (blistering)
and verrucous (wart-like) stages are inflammatory,
while the pigmentary and atrophic stages are
ordinarily not inflammatory.
The vesicular stage is seen in almost all cases.
It is usually seen at birth, but may be congenital,
generally most noted during the first 6-12 weeks of
life and overlaps with the verrucous stage that peaks
while the vesicular lesions are subsiding. The
vesicular lesions generally clear spontaneously,
sometimes going from vesicles to pustules that
rupture to form crusts in hours to days but may take
from 1-4 weeks to clear. These lesions may
reactivate in localized crops in certain patients after
infections, immunizations, or after trauma to the
area. Older patients may experience the same
recurrence of lesions, but usually with erythematous
whorls without any vesicles. The lesions may be
pruritic and can result in post-inflammatory
hyperpigmentation, unassociated with the
hyperpigmentation stage of the disease process.
Incontinentia pigmenti
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Most patients progress, and overlap, with the second stage, the
verrucous phase. This is manifested by 0.5mm – 1.0mm verrucous
papules and nodules that develop as the vesicular stage is waning, but
may present having developed without any vesicular lesions being
noted. These warty lesions generally are noted in a linear pattern on one
or more of the extremities, most notably on the dorsum of the hands and
feet. But for the linear pattern of development and their great numbers,
as well as their distribution, these lesions could be clinically confused
with common warts. These lesions are histologically, and by nature,
inflammatory, but on clinical inspection, very little inflammation may be
noted. The verrucous lesions generally resolve in 1-2 years, but may
persist into the patient’s teen years resolving with a hyperpigmentation
independent of the pigmentary and atrophic changes seen in stages 3
and 4.
The hyperpigmentation of the third stage is seen in just about all
patients, beginning at 3-6 months of life. In contrast to the vesicular and
verrucous lesions, the pigmentary changes are generally truncal in
distribution and not proceeded by inflammatory changes. The tanbrown/blue-gray/slate-gray/blue-brown pigmentary lesions are
characteristically asymmetrical. They appear as linear, swirled, streaky,
and serpiginous patterns and can look artificially induced. The bands of
pigmentary patterns may be purpuric appearing at onset and can raise
the question of child abuse. The pigmentary patterns generally intensify
during the first few years of life and then gradually fade and become
persistent for years. Two-thirds of patients see resolution of the
pigmentary lesions. If a biopsy of the pigmented area is undertaken, an
incontinence of pigment is seen, thus the name of the syndrome:
Incontinentia pigmenti. Since the pigment incontinence does not follow
the pattern of the vesicular or verrucous stage lesion, it is not
considered just a post-inflammatory hyperpigmentation phenomenon.
VERRUCOUS STAGE
between ages 2 and 8 weeks with warty, keratotic linear papules and plaques
• Stage 2: Verrucous
• Wart-like or pustular
lesions
• Thick crusts or
scabs form over
healing blisters
• Lesions may be
darker in skin colour
(hyperpigmentation)
• May be present at
birth but in 70-80%
of patients evolves
after the first stage
• May last for months,
but rarely longer
than a year
Incontinentia pigmenti
• IP in an affected
female; stage II:
the verrucous
(“warty”) stage.
The lesions to
not necessarily
arise in the same
place as those of
stage I.
Hyperpigmented stage
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Stage 3: Hyperpigmented
Skin is darkened in a swirled
pattern
Pigmentation ranges from
blue-grey or slate to brown
Present at birth in 5-10% of
patients but usually appears
within the first few months of
of life in 90-98% of patients
Darkened patches may or
may not be related to areas
affected in stage 1 and 2
Heavy pigmentation tends to
fade slowly with increasing
age
Hyperpigmented lesions in a
linear and whorled pattern on a
13-month-old girl with
incontinentia pigmenti.
Incontinentia pigmenti
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@" IP in an affected female with stage III "rash
@ An adult with reticulated pigmentation patterns
Incontinentia pigmenti
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The fourth stage characterized by hypopigmentation and atrophy is
seen in less than one-third of patients. The atrophic streaks, commonly
hypopigmented are seen on the arms, thighs, trunk, and particularly the
calves of affected individuals, but the atrophy and hypopigmentation is
usually most prominent on the extremities, especially the legs. These
changes can persist into adulthood and may be the only manifestation of
the syndrome available for diagnosis and subsequent appropriate genetic
counseling.
Even though the cutaneous findings are most prominent and oft times
diagnostic, it’s imperative to remember that involvement of the teeth,
eyes, or central nervous systems more often lead to morbidity. Teeth
abnormalities occur in about two-thirds of patients with deciduous and
permanent teeth both being affected with conical malformations of the
crowns of the incisors, canines and bicuspids as well as a decreased
number of teeth and/or delayed eruption of teeth.
Cicatricial (scarring) alopecia is seen in one-third to two-thirds of patients
and occurs most often at the vertex of the scalp. The alopecia area does
not necessarily coincide with prior vesicular or verrucous lesion
involvement. With or without hair involvement, up to 50% of patients may
experience nail abnormalities or even distal phalanges bone changes
noted on X-ray.
Vascular compromise may lead to retinal or cerebral infarction which can
cause partial or complete blindness or strokes. Strabismus as well as
cataracts, optic atrophy, retinal neovascularization or detachment can
occur. A small percentage of patients may even experience bilateral
blindness. About 20% of patients with incontinentia pigmenti will have
major eye abnormalities, with approximately one-third of patients having
some ocular pathology. Ocular examination in infants with incontinentia
pigmenti should be done monthly during the first four months and then
every three months through the first year of life. Ophthalmological exams
should continue twice yearly to age three, and then annually thereafter.
Hypomelanosis of Ito
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Stage 4: Atrophic/ hypopigmented
Scar-like lesions develop during adolescence and
persist into adulthood
Occur in 30-75% of patients
Appear as pale, hairless patches or streaks
In 1952, a Japanese dermatologist named
Ito described a 21-year-old woman with
hypopigmented cutaneous whorls and
streaks. As the distribution of the
hypopigmentation was analogous to that of
the hyperpigmented streaks observed in
incontinentia pigmenti, he called the
disorder ‘incontinentia pigmenti
achromians’. To avoid confusion of these
two unrelated entities, the preferred
terminology later became ‘hypomelanosis
of Ito’ (HI).
HI is a descriptive term, rather than a
diagnosis. It has been used for a phenotype
with unilateral or bilateral hypopigmented
streaks and whorls that follow the lines of
Blaschko and which are present at birth or
become apparent within the first 2 years of
life There may be associated systemic
findings.
Recently, the terms ‘nevoid
hypopigmentation,’ ‘mosaic
hypopigmentation’ or ‘segmental
pigmentary disorder’ with or without
systemic anomalies, were adopted to better
reflect the heterogeneous nature of this
group of disorders.
Hypomelanosis of Ito
Incontinentia pigmenti
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@ A 20-day-old female neonate with incontinentia pigmenti. Bullae, vesicles, and
verrucous lesions are seen on the lower extremities and buttocks
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@ A 27-day-old female neonate who first presented with incontinentia pigmenti when
she was aged 20 days. Note the verrucous eruptions with brownish pigmentation in a
streaky linear pattern on the left leg
Incontinentia pigmenti
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Stage 1: vesicopustules, following the lines of Blaschko
Stage 2: Linear verrucous
plaque, following the lines
of Blaschko
Incontinentia pigmenti
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Classically, there are
vesicles and bullae on an
erythematous base,
arranged in a linear
pattern along Blashko's
lines. These vesicles are
superseded by red, often
warty papules and
plaques which, in turn,
are supplanted by brown
lentiginous lesions in a
similar pattern.
All stages can be present
simultaneously.
A peripheral eosinophilia
is common in the
inflammatory stages.
There are often
associated dental, ocular
and CNS defects.
Histopathological findings
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Histopathological findings change according to the phase in which the lesions are
presented .The name IP is derived from the common histologic finding of incontinent
melanin in the superficial dermis. . In the first phase, intraepidermal spongiosis with
eosinophilic, neutrophilic and rarely basophilic inflammatory infiltration may be
observed. Large dyskeratotic cells are usually present. The verrucous stage presents
acanthosis, hyperkeratosis and papillomatosis. Eosinophils can be seen eventually.
Stage 3 shows prominent pigmentary incontinence. The atrophic phase is
characterized by absence of pigment in the epidermis and lack of eccrine glands.
The hair may also be affected in IP. Scarring alopecia, usually on the vertex, is the
most common manifestation of hair involvement . The absence or hypoplasia of
eyebrows and eyelashes may also occur. In addition, the hair can be sparse in
infancy and later have a coarse appearance and brittleness.
Ungual alterations can affect all nails of the hands and feet or just a particular nail,.
Nail dystrophy can vary from fragile and brittle nails, with longitudinal or transverse
slits up to hyperkeratosis and onycholysis. Rarely, in mild cases, nail changes may be
the only manifestation of IP. Periungual and subungual keratotic tumors, associated
with pain, bone deformities and lytic lesions involving the underlying phalanges may
also be seen, usually in older children and adults. The fingernails are more commonly
affected
incontinentia pigmenti
Histopathology showing eosinophilic spongiosis and acanthosis
IJD : 2013 : 58 : 4 : 328
Diagnostic Criteria for IP in the absence of familial history
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The diagnostic criteria for IP were divided into 2 groups: one group with negative family history
and another with positive family history in a first-degree relative.
In the absence of familial history, the presence of at least one major criterion * is required while
the presence of minor criteria ** supports the diagnosis of IP. On account of their high incidence,
the complete absence of minor criteria leads to uncertainty in diagnosis
Major criteria:
- Typical neonatal vesicular rash (erythema, vesicles, eosinophilia)
- Typical hyperpigmentation (especially on the trunk, following the lines of Blaschko, disappearing
in adolescence)
- Linear atrophic alopecic lesions
**Minor Criteria:
- Dental abnormalities
- Alopecia- Wooly hair, nail abnormalities
- Retinal disorders
If NEMO mutation status is unknown, and incontinentia pigmenti is not present in a first-degree
female relative, at least 2 major criteria or 1 major and at least 1 minor criteria are required to
make the diagnosis of sporadic IP.
If NEMO mutation status is unknown but incontinentia pigmenti is present in a first-degree female
relative, then any single major criteria or 2 minor criteria are required to make the diagnosis.
If NEMO mutation has been confirmed, the presence of any 1 major or minor criteria is required to
make the diagnosis
Diagnostic criteria for IP in the presence of familial history
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***Criteria:
- Suggestive history or evidence of typical rash
- Cutaneous manifestations of IP: hyperpigmentation, scaring lesions,
atrophic lesions, and linear atrophic lesions with absence of hair, alopecia
on the vertex
- Dental abnormalities
- Wooly hair- Retinal disorders
- Multiple abortions of male fetuses
Treatment
IP vesicopustular lesions often cause concern and because they appear in
the neonatal period, other dermatoses with greater morbidity should be
excluded, such as impetigo, neonatal congenital bullous dermatoses and
autoimmune blistering. Cutaneous manifestations of IP do not require
specific treatment, since spontaneous resolution of the lesions usually
occurs. The use of topical and systemic antibiotics for vesicular lesions is
not recommended.
Incontinentia pigmenti
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Stage 3: Hyperchromic and atrophic spots, following the lines of Blaschko
Atrophic and hypochromic lesions,
following the lines of Blaschko
Incontinentia pigmenti forming along Blaschko's lines in a 3-year-old girl.
Incontinentia pigmenti
Incontinentia Pigmenti (mutated NEMO gene), XLD
Hair affection in incontinentia Pigmenti
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Area of scarring alopecia on the vertex of the scalp
Hair affection in incontinentia Pigmenti
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Hair. Alopecia may occur on the
scalp and also on the trunk and
extremities. Patchy alopecia of
the scalp may correspond to
areas of scarring left from
blistering in stage I, but may also
occur in individuals who have
had no stage I or II lesions on
the scalp. Alopecia occurs in
areas of skin hypopigmentation
as part of stage IV skin changes.
Scalp hair may be thin or sparse
in early childhood. Hair may also
be lusterless, wiry, and coarse,
often at the vertex in a "woollyhair nevus." Areas of alopecia
may be very small, unnoticed by
the affected individual and
difficult to find, particularly when
covered by other scalp hair.
Sparse eyelashes and eyebrows
are also reported
Incontinentia Pigmentifinger nail dystrophy
Incontinentia Pigmenti
• Nails. Nails can be
dystrophic (i.e., lined,
pitted, or brittle). These
changes often resemble
fungal infections of the
nails. Dystrophic nails
are most commonly
associated with stage II.
The nail changes may
be transient, but a
single, chronic,
longitudinal ridge in the
nail was present
Incontinentia Pigmenti
Actas Dermosifiliogr.2013;104:451
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Different clinical
aspects of
incontinentia
pigmenti.
A, Vesicular phase
in a neonate.
B, Linear
hyperpigmented
lesions on the legs
in a later stage.
C, Dental agenesis
and presence of
cone-shaped teeth.
D, Nail dystrophy,
with trachyonychia
and pitting of the
nail plate.
INCONTINENTIA PIGMENTI:
It is NOT just a skin
condition!
Questions
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6. IP skin lesions usually occur on:
a) The lines of Blaschko
b) Areas of trauma
c) In mucosae
@@@d) On knees and elbows
7. The following symptoms may occur in the IP, except:
a) Onychodystrophy
@@@b) Alopecia on the vertex
c) Ichthyosis
d) Brittle and dull hair
8. Which skin lesions can occur in adults with IP?
@@@a) Linear hypertrophic plaques
b) Linear hypopigmented macules
c) Hyperpigmented macules
d) Hypochromic spots with altered sensitivity
OPHTHALMOLOGIC FINDINGS
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Ophthalmologic findings occur in 20-35% of patients, and asymmetric involvement is
common. Retinal vascular changes, optic atrophy, and developmental defects may be
seen. Loss of visual acuity and blindness are significant complications. Blindness has
been reported to develop in 7% of incontinentia pigmenti patients.
Ophthalmologic manifestations may become evident within the first few weeks to
months of life and may progress rapidly to permanent visual deficits.
Retinal vaso-occlusive events with resultant ischemia are believed to be the primary
mechanism underlying ocular pathology. Retinal manifestations include retinal
detachment, proliferative retinopathy, fibrovascular retrolental membranes, foveal
hypoplasia, vitreous hemorrhages, and atrophy of the ciliary body. A bimodal
distribution of retinal detachment has been reported, with tractional detachment
occurring at a median age of 1.5 years and rhegmatogenous detachment occurring in
adults with a median age of 31.5 years.
Nonretinal manifestations include strabismus, optic nerve atrophy, conjunctival
pigmentation, microphthalmia, vortex ("whorl-like") keratitis, cataracts, iris hypoplasia,
nystagmus, and uveitis
Due to the severity of lesions, a screening program is imperative for children with
diagnosis of IP, allowing the early detection and therapeutic intervention. If untreated,
these lesions may progress to retinal detachment and subsequent blindness.
Treatment
Several studies have reported the benefits of laser photocoagulation or cryotherapy
in ischemic regions of the retina in order to stop the progression of vasculopathy. On
the other hand, at the stage of retinal detachment, surgery is rarely successful.
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OPHTHALMOLOGICAL changes
OPHTHALMOLOGICAL changes
a) Skin lesions on the trunk and the arm; (b) fundus right eye shows abnormally dilated and
tortuous posterior pole vessels, exudative retinal detachment and multiple hemorrhages; (c)
right eye, 1 month after laser with residual lipid exudates and nasal falciform fold; (d) right eye,
6 months after laser shows nasal falciform fold and submacular scar (arrow)
Indian J Ophthalmol [serial online] 2011 [cited 2016 May 24];59:255
Anterior segment biomicroscopy showing diffuse cortical lens opacities (cataracts) in a 32
years-old patient. View by direct illumination (a) and retro-illumination (b)
Fundoscopy showing (a) extensive formation of fibrous tissue at the posterior pole with flat retinal
detachment and alterations in the vascular path. Vascular attenuation is seen with arterial narrowing.
Pallor of the papilla, and (b) alterations of the retinal pigment epithelium. There is a diffuse mottled
aspect, caused by clusters of rarefied pigments. Above the papilla, there is an area of retinal pigment
hypertrophy
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13. Regarding the ophthalmologic involvement in Incontinentia Pigmenti Syndrome it can be affirmed that:
a) It is usually severe and disappears over the years
b) It usually occurs bilaterally
@@@c) It is usually associated with neurological disorders
d) It occurs in up to 15% of the cases
14. Among the conditions below, which is not related to IP?
a) Retinal detachment
b) Strabismus
c) Cataract
@@@d) Iris cyst
15. The physiopathological process that determines ocular manifestations in Bloch Sulzberger syndrome is still poorly elucidated. However, some
observations about it are described:
I) The ischemic process and the angiogenic response are similar to those of prematurity retinopathy
II) Strabismus is usually secondary to retinal pathology
III) Retinal detachment is secondary to the presence of transver se vessels in the macula
According to the statements above, it can be said that:
a) I and II are correct
@@@b) II and III are correct
c) I and III are correct
d) All are correct
16. In a 30 days-old patient diagnosed with Incontinentia Pigmenti, it is recommended:
I) Ophthalmological examination as soon as possible
II) Ophthalmologic examinations monthly until about 4 months
III) Ophthalmologic examinations with six-month intervals until one year old
Among the statements above it is correct to say that:
a) I and III are correct
b) II and III are correct
c) I and II are correct
@@@d) All are correct
17. Regarding ophthalmologic treatment and visual prognosis in patients with IP, we cannot affirm that:
a) Laser photocoagulation or cryotherapy have shown satisfactory results
b) Retinal detachment surgery has good results.
c) Visual prognosis is usually good for a child with no ophthalmologic findings up to 1 year of age
@@@d) Treatment, when necessary, should be instituted early
NEUROLOGIC FINDINGS
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Central nervous system disorders in patients with IP can have a major
impact on quality of life. In general, the prevalence of CNS symptoms is
approximately 30%. It has been hypothesized that there is a correlation
between the severity of ophthalmologic findings and the neurological
phenotype.
Neurological manifestations associated with IP are varied, ranging from a
single episode of seizure to psychomotor retardation, intellectual
impairment, hemiplegia, epilepsy, cerebellar ataxia, microcephaly, neonatal
encephalopathy, encephalitis and neonatal and childhood stroke.
The initial clinical neurological manifestation is reported by many authors as
"pseudo encephalitis" with acute neurological symptoms, sometimes
associated with a state of coma and apnea, simulating encephalitis.
Cerebral necrosis and multiple infarctions were reported.
Ischemic cerebrovascular accidents (CVA) seem to be the basis of
neurological manifestation in the neonatal period.. Despite the sporadic
description of large artery occlusion, microvascular occlusion appears to be
an important pathogenic mechanism. A critical analysis of the available data
suggests that the disease affects mainly small and medium caliber arteries
in the newborn brain.
NEUROLOGIC FINDINGS
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Central nervous system. Seizures, intellectual disability, and other CNS abnormalities have
been reported in approximately 30% of individuals with IP . The actual incidence of neurocognitive
disability is unclear because mildly affected cases without neurocognitive problems may not come
to medical attention . Neurocognitive disability is more common in simplex than in familial cases,
presumably because mildly affected family members are identified . Males with IP are more likely
than females to have neurologic abnormalities. In general, neurologic abnormalities in patients
with IP appear to be associated with underlying CNS vasculopathy .
Seizures. Seizures in IP range from a single episode in a lifetime to chronic epilepsy. The type of
seizure varies because the stroke etiology may involve any part of the cerebrum.
Intellect. The majority of individuals with IP, both male and female, are intellectually normal . The
incidence of intellectual disability or developmental delays in males who meet the IP diagnostic
criteria is approximately25 -3O%. In males, co-occurrence of a 47,XXY karyotype may complicate
the intellectual phenotype of IP.
Brain anomaly. Primary brain anomalies are rare. The following have been seen in individual
patients: agenesis of the corpus callosum with an occipital encephalocele ; polymicrogyria ; and
gray matter heterotopias
Evidence that IKBKG pathogenic variants may cause abnormalities in microvasculature supports
the theory that CNS dysfunction is secondary to vascular problems that result in transient
ischemic attacks or full-blown hemorrhagic strokes . Neurovascular abnormalities are most
common in the first year of life with only a handful of patients reported after that, and only three
after age four years .
Periventricular leukomalacia is documented in 27 of 43 MRIs in patients with IP who have
neurocognitive disabilities, especially seizures, and subcortical white matter changes were also
seen commonly. Some patients have subsequent cystic changes. Myelination delays and
ventricular dilation have also been reported
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9. The prevalence of neurological involvement in IP is about:
@@@a) 5%
b) 30%
c) 50%
d) 95%
10. The most common neurologic manifestation is:
a) Seizure
b) CNS tumor
@@@c) Intracranial hypertension
d) Brain atrophy
11. The severity of neurologic symptoms in IP relates to the degree of which involvement?
a) Ophthalmological
b) Dental
c) Dermatological
@@@d) Hematologic
12. In IP, the following neurologic findings may be present, except:
a) Microcephaly
@@@b) Bulging fontanelle
c) Hypoplasia of the corpus callosum
d) Mental retardation
NEUROLOGIC FINDINGS
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Neurologic complications may result in part from microvascular vaso-occlusive
ischemic events involving the CNS, and recurrent acute stroke may occur.Extensive
cerebral infarction involving small and medium-sized cerebral arteries may result in
destructive encephalopathy. Involvement of the cerebral hemispheres, cerebellum,
and corpus callosum may occur. Progressive periventricular hemorrhagic infarcts
have been reported. Other reported brain MRI abnormalities include periventricular
and subcortical white matter disease, hypoplasia of the corpus callosum, cerebral
atrophy, and cerebellar hypoplasia.In addition to ischemic vascular insult,
inflammation and apoptosis are believed to contribute to the development of
neurologic sequelae.
Interestingly, resolution of cortical and subcortical white-matter destructive lesions
have been reported in several infants with incontinentia pigmenti.
Other neurodevelopmental manifestations include developmental delay, mental
retardation, learning disabilities, ataxia, spastic paralysis, microcephaly,
porencephaly, and periventricular cerebral edema
• Treatment
• There is no specific treatment for IP's neurological symptoms.
The treatment of seizures is only symptomatic. .
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DENTAL FINDINGS
• Dental and oral abnormalitie are seen in 50-80% of patients and can
involve both deciduous and permanent teeth. Dental anomalies are
permanent and thus serve as a very useful diagnostic finding in
older patients. Delayed eruption of dentition, partial anodontia,
hypodontia, and conical or pegged teeth are the most common
dental findings. Poor enamel quality leading to an increased
incidence of dental caries and early dental loss has been reported
historically, but this association has been questioned. The most
common oral anomalies are cleft palate and high-arched palate. An
increased prevalence of dental malocclusion and facial asymmetry
has also been reported.
• Dental features in IP may be mistaken for other diseases such as
congenital syphilis or ectodermal dysplasia. Although there are
subtle differences in tooth morphology distinguishing these
disorders, cutaneous lesions associated with systemic
manifestations and laboratory findings are useful to establish the
correct diagnosis.
Deciduous dentition with increased overbite, cone-shaped maxillary right
central incisor, malformed lower anterior teeth and dental agenesis
Mixed dentition with atresic maxilla, posterior crossbite on the right side,
presence of irregularities on incisal margins of upper and inferior incisors and
dental agenesis
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@ Incontinentia pigmenti. Hypodontia and conical teeth
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@ Abnormal dentition in a boy with incontentia pigmenti.
Incontinentia pigmenti
Journal of Indian Society of Pedodontics and Preventive Dentistry, Vol. 33, 2015, 74-77
Incontinentia pigmenti
photograph shows structural enamel and
dentin malformation of the maxillary
anterior teeth
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Incontinentia pigmenti
: 2010 : 53 : 2 : 302
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Skeletal malformati on of the toes and nails
Talon cusps of maxillary anterior teeth
Incontinentia pigmenti
: 2010 : 53 : 2 : 302
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The skin biopsy shows a mild melanin inconti nence in the dermis
Skin biopsy of the legs shows hyperpigmentation
and vacuole formation of basal cells in the
epidermis
Incontinentia Pigmenti
Incontinentia Pigmenti
Incontinentia Pigmenti
Questions
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18. The following may be skeletal problems of the stomatognathic system,
associated with Incontinentia Pigmenti syndrome:
a) Transverse maxillary atresia associated with oligodontia in the maxilla and
mandible
@@@b) Alternatives a and c are correct
c) Facial asymmetry as hemifacial hypoplasia
d) None of the alternatives are corrects
19. Select the wrong alternative. The following are dental problems commonly
associated with Incontinentia Pigmenti syndrome:
a) Missing teeth
@@@b) Conoid teeth
c) Giant anterior teeth
d) Delayed tooth eruption
20. Because of its dental characteristics, Incontinentia Pigmenti syndrome can
be confused with other congenital diseases. Among these are:
@@@a) Syphilis
b) Mandibular Congenital Dysplasia
c) Ectodermal Dysplasia
d) Alternatives a and c are correct
OTHER ABNORMALITIES
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OTHER ABNORMALITIES
Other findings have been reported in patients with IP. Breast abnormalities may occur in 1% of
affected patients and include @ supernumerary nipples, hypoplastic nipples, breast hypoplasia
and abnormal nipple pigmentation. @ Skeletal deformities affect up to 20% of patients and include
scoliosis, hemivertebra, spina bifida, syndactyly, ear defects, and increased number of ribs,
chondrodystrophy, clubfoot, short stature and dwarfism. @ Oral anomalies include ogival palate,
soft palate hypoplasia, cleft palate and cleft lip. More rarely, @ cardiac malformations can occur
as ventricular endomyocardial fibrosis, tricuspid insufficiency and pulmonary hypertension.
@ Eosinophilia (as high as 65%) in the blood count may be present in up to 88% of patients with
IP.
SPEECH THERAPY CONTRIBUTION IN THE ASSISTANCE OF IP PATIENTS
Patients with IP, as described above, may present dental abnormalities, oral malformations, CNS
alterations, delayed neuro-psychomotor development and hearing loss. All of these conditions are
directly related to the development of speech, language, hearing and swallowing functions. In
general, these findings persist throughout the patient's life. Therefore, speech therapy has an
important contribution at the time of the diagnosis and management of patients with IP.
In particular, children with IP may even have difficulties in the development of learning skills such
as reading and writing, since cognitive, auditory and neurological disorders may occur.
Therefore, IP is a multisystem syndrome in which a multidisciplinary approach is very important.
There is no doubt that the cutaneous manifestations are characteristic and definitive for the
diagnosis and, therefore, should be known to all dermatologists. During routine outpatient visits,
identification of possible interfaces with genetics, dermatology, ophthalmology, neurology and
dentistry generates a multidisciplinary, comprehensive and better quality care for patients with IP.
Pathophysiology
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Pathophysiology
IP is due to mutation in the IKBKG gene (approved name: Inhibitor of the Kappa light polypeptide
gene enhancer in B-cells, Kinase Gamma) which is located on the X chromosome at position
q28. This gene is also known as NEMO (Nuclear Factor κβ Essential Modulator) or IKK-γ
(Inhibitor of nuclear factor Kappa-B Kinase, subunit gamma). This gene codes for one of three
subunits of the IκB kinase enzyme complex which is part of the NF-κB cascade. NF-κB plays a
critical role in regulating inflammation and the immune response to infection. An approximately
11.7-kb deletion in the IKBKG gene that removes exons 4 through 10 is the cause of the majority
of IP mutations. This gene is involved in activating Nuclear Factor – κβ (NFκβ) which acts as a
transcription factor, and is important in activating genes necessary for the production of cytokines
and chemokines, as well as providing anti-apoptotic effects.
With this mutated gene, endothelial cells and other cells throughout the body can over-express
chemotactic factors specific for eosinophils, explaining why serum eosinophilia is common in IP
patients. The epidermal skin lesions also show extensive involvement of eosinophils. It appears
that the eosinophils, combined with other factors, lead to extensive inflammation, affecting not
only the skin, but also endothelial cells. It is believed that this inflammation leads to vasoocclusion, which results in ischemia, causing both the retinal and neurologic manifestations of
IP. However, to complicate matters, there is little evidence that the typical inflammatory pathology
in the skin also occurs in the retina; furthermore, there is also a lack of evidence showing vasoocclusion in the skin lesions.
The ocular manifestations are the result of vaso-occlusions in the retinal arteries, resulting in
subsequent ischemia. Avascular areas in the periphery of the retina develop secondary to this
hypoperfusion and ischemia. As in many ischemic retinal conditions, neovascularization occurs
with damaging sequela.
Likewise, in the CNS, the cerebral and cerebellar atrophy as well as other neurologic sequela are
believed to be due to vaso-occlusive ischemia and nerve cell death.
Pathophysiology
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It is X-linked dominant, the vast majority of cases are seen in female individuals. The recently
discovered genetic mutation in IP lies in the NEMO/IKK-gene that encodes a protein important in
signaling pathways of apoptosis and inflammatory responses. Incontinentia pigmenti (IP) or
Bloch-Sulzberger syndrome is a rare, X-linked dominant inherited genodermatosis, usually lethal
in males even in the prenatal period. IP is caused by mutations in the NEMO gene (IKK-gamma),
located in Xq28 locus. The NEMO protein is one subunit of a complex multi-protein kinase which
is crucial for the activation of the transcription factor NF-kappa B, essential in the regulation of
inflammatory immune and apoptotic pathways.
Most cases of IP are caused by mutations in NEMO, and new genomic rearrangements are
responsible for 80% of the new mutations. In 80% of the cases there is a deletion of exons 4 to 10
on the NEMO gene. In addition, point mutations, such as nonsense mutations and those with
change in direction can be found in exons 2 to 10. Also described are insertions and deletions,
some of them leading to a shift in the reading frame. As a result, activation of NF-kappa-B is
defective in IP cells. The presence of one mutation in NEMO causes an alteration in cytokine
production, markedly during the first year of life, which may explain the inflammatory
manifestations in skin morphology.
The IP penetrance is 100%, but its expression is highly variable even within families. Cells
expressing the mutated X-chromosome are selectively eliminated around the time of birth. The
majority of affected women present a nonrandom (skewed) X-chromosome inactivation in
peripheral blood leukocytes and fibroblasts. In 98% of these women a skewed model of Xchromosome inactivation can be observed, whereas in the normal population only 10% present
skewed inactivation.
Among men, IP is classically considered lethal. However, in some men a karyotype 47, XXY and
the skewed inactivation of X-chromosome provide protection against the morbid effects of the
mutation. Furthermore, the presence of mosaicism or less deleterious mutations in NEMO may
allow some men to survive.
X-linked inheritance patterns result from mutations located on the X Chromosome.
Females have two X chromosomes of which only one carries a mutation in X
chromosome
Males with IP
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Males with IP. Although IP has been identified as a "male-lethal" disease, there are welldocumented male cases..
Survival in a male is mediated through one of two mechanisms:
1.47,XXY karyotype, estimated to be present in 7% of males with IP
2. Somatic mosaicism
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Low-level mosaicism of 46,XY/47,XXY was demonstrated in one male only by interphase FISH using X and
Y probes . The affected child did not have a demonstrable IKBKG pathogenic variant.
Some males also exhibit "segmental" IP (lesions restricted to a single limb), a finding consistent withsomatic
mosaicism.
The reasoning behind male lethality in IP is that male conceptuses that inherit an
X chromosome with a mutated IKBKGgene lack the normal protein necessary for viability. The
precise mechanism of male lethality is unknown , although mouse models suggest that liver failure
plays a role .
Pathogenic variants that produce a milder form of the condition are always associated with
immunodeficiency (known as X-linked hypohidrotic ectodermal dysplasia and immunodeficiency
(HED-ID) in males . Only one male has been reported with HED-ID and also clinical findings of IP
in association with the c.1167dupC IKBKG variant .
Life expectancy. For persons without significant neonatal or infantile complications, life
expectancy is considered to be normal.
Reproductive fitness. Women with IP are at increased risk for pregnancy loss, presumably
related to low viability of male fetuses. It is common for women with IP to experience multiple
miscarriages, often around the third or fourth month of gestation. Fertility does not otherwise
appear to be impaired; conception of an unaffected fetus would be expected to result in an
uncomplicated pregnancy and delivery
Questions
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1. Most cases of incontinentia pigmenti are caused by wich type of mutation?
a) Small insertions on NEMO gene
b) Point mutations throughout NEMO gene
c) Large deletions on NEMO gene
@@@d) Mutations on the promotion region of NEMO gene
2. On the inheritance pattern of pigmentary incontinence, it is incorrect to state that:
a) Women are more often affected, since the pattern of inheritance is X-linked dominant
b) The disease is usually lethal in males.
c) There is no difference in the expression of the disease when men and women are compared.
@@@d) The penetrance of the disease is 100%
3. The survival of some men with pigmentary incontinence can be explained by:
@@@a) Mosaicism in men 47, XXY
b) Protection by the non-expression of the mutated gene in men 46, XY
c) Non-penetrance of the disease in men
d) Non-random inactivation of the X
4. About the function of the protein encoded by NEMO gene, it can be stated that:
a) Increased expression of NEMO is responsible for the presence of the observed clinical phenotype
b) It is a subunit of a complex multi-protein kinase, which is essential for the activation of the transcription factor
NFkappa B in response to a variety of stimuli, including proinflammatory cytokines
c) The presence of NEMO mutations leads to changes in cytokine production after the onset of puberty
@@@d) The alteration NEMO expression and hence the non-activation of NF-kappa-B is not associated with
inflammatory manifestations in the morphology of the skin
Genotype-Phenotype Correlations
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Pathogenic sequence variants in IKBKG, mainly in exon 10 (including missense, single base insertion/deletion causing frame shift, and
nonsense mutations), are associated with a milder IP phenotype in females and a lower risk of miscarriage of male fetuses. Indeed, most
of these variants allow survival of males with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) and HED-ID with
osteopetrosis and lymphedema (OL-HED-ID). These pathogenic variants result in impaired but not absent NF-kappaB signaling .
Penetrance
Incontinentia pigmenti has high penetrance. Most persons with IP appear to express the phenotype within a few months after birth.
Expressivity, however, is highly variable. In addition, the skin findings can resolve over time and may be indistinguishable from other skin
conditions with age. Furthermore, the dental, hair, and nail abnormalities can be managed cosmetically such that an affected adult woman
may not have clinically evident diagnostic findings on physical examination.
Nomenclature
Some individuals with structural abnormalities of the X chromosome manifest swirled hyperpigmentation even though their Xchromosome abnormalities do not involve the IKBKG locus (Xq28). This observation led to the designation of a separate condition,
incontinentia pigmenti type I (IP type I), with a suggested locus at Xp11. Detailed research failed to document consistent linkage to Xp11
or a consistent phenotype. Thus, the designation "IP type I" is thought to be incorrect .
Prevalence
As of 2010, about 1000 female IP cases had been reported. The literature of both female and male cases continues to grow, especially
with further delineation of the underlying molecular mechanisms. The female:male ratio is 20:1 [Orphanet].:
Genetically Related (Allelic) Disorders
Other phenotypes associated with mutation of IKBKG:
X-linked hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) (also known as ectodermal dysplasia, anhidrotic, with
immunodeficiency [EDA-ID])
HED-ID with osteopetrosis and lymphedema (OL-HED-ID)
HED-ID and OL-HED-ID affect males exclusively. They are caused primarily by missense mutations (although in-frame deletions, frame
shifts, and splicing and other mutations are known) within IKBKG that result in impaired, but not absent, nuclear factor-kappaB (NF-kappa
B) signaling. A list of the IKBKG pathogenic variants associated with HED-ID has been reported .
Note: HED-ID and OL-HED-ID are distinct from the X-linked form of hypohidrotic ectodermal dysplasia that is caused
by mutation or deletion of EDA (see Hypohidrotic Ectodermal Dysplasia).
Other IKBKG-related phenotypes:
Atypical mycobacteriosis, X-linked , manifest as combined immunodeficiency with early susceptibility to pyogenic bacteria and later
susceptibility to mycobacterial infection, was reported in association with particular IKBKG pathogenic variants in males .
It was reported on X-linked susceptibility to mycobacterial diseases characterized by susceptibility to infection of weakly virulent
mycobacterial species (e.g., bacillus Calmette-Guérin [BCG]) in association with missense IKBKG mutation in males.
Incontinentia pigmenti
Recurrent Deletion In
The Ubiquitously
Expressed NEMO IKK
Gamma
Differential Diagnosis
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A diagnosis other than incontinentia pigmenti (IP) should be considered when an individual has skeletal involvement (other than
secondary to neurologic deficit), gross neurologic deficit, severe alopecia, atypical hyperpigmentation, or gross hypopigmentation. Body
segment asymmetry is not usually associated with IP; however, one individual with IP and transverse terminal upper acromelia has been
reported .
The differential diagnosis for the skin manifestations of IP varies by stage. Because a child with IP may have an infectious comorbidity,
findings consistent with an infectious disease should be evaluated accordingly, regardless of the presence of IP.
Stage I – blistering stage. The following need to be considered]: congenital herpes simplex, varicella, staphylococcal or streptococcal
bullous impetigo, and (in severe cases) epidermolysis bullosa (seeDystrophic Epidermolysis Bullosa, Epidermolysis Bullosa Simplex).
The infectious conditions are typically associated with other signs of inflammation including fever and symptoms of systemic toxicity.
Scrapings and cultures of the lesions are diagnostic for the infectious diseases. Blistering lesions that appear after light trauma are
characteristic of epidermolysis bullosa. Diagnosis is established by analysis of a skin biopsy, transmission electron microscopy or
immunofluorescent antibody/antigen mapping, and molecular genetic testing.
Stage II – verrucous stage. The findings are not likely to be confused with other conditions, although a mild case of IP may resemble
simple warts or molluscum contagiosum. When the lesions are numerous and appear in the appropriate pattern, they are more likely to be
IP than either warts or molluscum contagiosum. Differentiating single IP lesions from warts can be difficult without a biopsy.
Stage III – hyperpigmented stage. The differential diagnosis includes any condition that leads to irregular areas of skin pigmentation or
other anomalies along the lines of Blaschko .
The most commonly confused diagnosis is hypomelanosis of Ito , which can demonstrate the same "swirled" pigmentation pattern . The
most significant difference is that in individuals with IP the hyperpigmented areas are abnormal, whereas in hypomelanosis of
Ito hypopigmentation is typical but patches of hyperpigmentation can also be observed. Hypomelanosis of Ito is often the result of
chromosomal mosaicism. Individuals with chromosomal mosaicism often have intellectual disability and congenital malformations,
including brain anomalies. Reports of individuals with hypomelanosis of Ito having IP may account for the higher incidence of intellectual
disability and CNS anomalies reported in individuals . Individuals with findings suggestive of hypomelanosis of Ito warrant evaluation for
chromosomal mosaicism by a blood karyotype, and if that is normal, by skin fibroblast karyotype .
Stage IV – atretic stage. The atretic skin areas can resemble scarring, vitiligo (with localized alopecia), or any other condition
demonstrating hypopigmentation and localized alopecia. Differentiation is based largely on medical history. Vitiligo is progressive and the
hypopigmented areas can be surrounded by areas of hyperpigmentation. Vitiligo is not preceded by the other stages of IP or
accompanied by non-cutaneous manifestations. Piebaldism , an autosomal dominant form of hypopigmentation in which manifestations
are limited to the skin, is most often present at birth and does not progress.
The differential diagnosis of other manifestations of IP includes the following disorders:
Naegeli syndrome , a rare autosomal dominant disorder affecting the skin and skin derivatives, resembles IP, but also includes
hyperhidrosis and punctate hyperkeratosis of the palms and soles. Unlike IP, Naegeli syndrome does not evolve through different stages
of skin involvement. Naegeli syndrome is extremely rare; an individual with linear, wart-like lesions is more likely to have IP. Pathogenic
variants in KRT14 cause Naegeli syndrome.
Retinal neovascularization is observed in retinopathy of prematurity and familial exudative vitreoretinopathy, which can be inherited in
an X-linked recessive manner as part of the Norrie disease spectrum (see NDP-Related Retinopathies) or in an autosomal
dominant manner (see Autosomal Dominant Familial Exudative Vitreoretinopathy). Skin findings are not present in these disorders
Management
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Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with incontinentia pigmenti (IP), the
following evaluations are recommended:
Physical examination with particular emphasis on the skin, hair, nails, and neurologic system to establish the
presence and extent of manifestations
Medical genetics consultation for diagnosis, treatment plan, testing, and family counseling
Involvement of a pediatric dermatologist for diagnosis, and for management of significantly involved cases
Prompt examination by an ophthalmologist familiar with IP and/or diseases of the retina for evidence of retinal
neovascularization
EEG and MRI if seizures, other neurologic abnormalities, or retinal hypervascularization are present
Magnetic resonance angiography, potentially useful in identifying cerebrovascular lesions if the neurologic deficit is
consistent with a stroke-like pattern
Developmental screening, with further evaluation if significant delays are identified
Treatment of Manifestations
Treatment includes the following:
@ Management of blisters in a standard manner (i.e., not opening them, avoiding trauma); topical treatment (e.g.,
medications, oatmeal baths) to relieve discomfort. Significant skin involvement may benefit from dermatology
management.
@Treatment of infections as for any other cellulitis
@ For retinal neovascularization that predisposes to retinal detachment, cryotherapy and laser photocoagulation
@ Standard treatment for retinal detachment
@ Referral to a pediatric neurologist for evaluation if microcephaly, seizures, spasticity, or focal deficits are present
@ Brain MRI in any child with functional neurologic abnormalities or retinal neovascularization
@ Referral to a pedodontist at age six months or when teeth erupt, whichever comes first. Dental implants have
been performed as early as age seven years (as in children with ectodermal dysplasia, who have similar dental
problems (see Hypohidrotic Ectodermal Dysplasia).
@ Referral to a speech pathologist and/or pediatric nutritionist if delayed or inadequate eruption of primary teeth
interferes with chewing and/or speech development
@ Appropriate developmental stimulation and special education as indicated for developmental delay
Management
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Prevention of Secondary Complications
Management in the newborn period is aimed at reducing the risk of infection of blisters using standard medical
management: not rupturing sealed blisters, keeping the areas clean while they are healing, and careful monitoring
for excessive inflammation and signs of systemic involvement.
The parents should be instructed about the possibility of retinal detachment particularly in children younger than
age seven years; any apparent changes in vision or any evidence of acquired strabismus should be evaluated
promptly. Head trauma may precipitate retinal detachment; therefore, any evaluation for head trauma should
include a thorough eye examination.
Surveillance
No schedule for eye examinations has been established, but the following has been suggested :
@ Monthly until age three to four months
@ Every six months between ages one and three years
@ Annually after age three years
@ Neurologic function should be assessed at routine visits with a pediatrician, pediatric neurologist, or
developmental pediatrician.
@Ongoing evaluation by a pedodontist or dentist is appropriate.
Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as
early as possible those who would benefit from initiation of treatment and preventive measures (routine eye
examinations).
@ If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic
status of at-risk relatives.
@ If the pathogenic variant in the family is not known, physical examination, including examination of the skin,
teeth, hair, nails, retina and CNS, can be used to clarify the disease status of at-risk relatives..
Pregnancy Management
Overall pregnancy health and management usually does not vary from normal. The risk of spontaneous abortion is
higher than population rates, but management of pregnancy loss is done in the standard manner. For women with
retinal problems, delivery management to minimize or eliminate labor should be considered to avoid retinal
detachment.
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Genetic testing
The IKBKG gene (previously NEMO) is the only known gene associated with IP. Approximately 65% of affected
individuals have an 11.7-kb deletion removing exons 4 – 10 from the IKBKG gene. Targeted mutation analysis are
available to look for this mutation. In addition to this deletion, other small IKBKG mutations have been found in
those with IP, most often occurring in exon 10. Sequence analysis can detect these mutations. Also, in females
with skewed lyonization in which the X chromosome with the mutant IKBKG allele is inactivated, X-chromosome
inactivation studies may be useful. In suspected males, karyotyping and fluorescence in situ hybridization to look
for evidence of 47,XXY may be done.
Laboratory testing
Eosinophilia may occur (as high as 65% of leukocytes) particularly in stages I and II.
Skin biopsy with histologic examination to evaluate for eosinophilic infiltration and/or extracellular melanin granules
may be helpful in confirming the diagnosis in an individual with borderline or questionable findings in whom
molecular genetic testing has not identified a disease-causing mutation. Skin biopsy for diagnosis is rarely needed
given the availability and sensitivity of genetic testing.
Genetic Planning
If a proband is identified, clinical examination of family members and genetic testing of the mother is warranted.
If a female has IP (IKBKG mutation), the risk of conceiving a fetus with IP is 50%. However, most affected males
die in utero, meaning that an affected mother has a near 33% probability to giving birth to either an affected
female, unaffected female, or unaffected male.
In parents without IP or an IP-related IKBKG mutation that have had a child with IP, the risk of a subsequent child
having IP is less than 1%.3
Prenatal testing
Prenatal diagnosis of fetuses with a family history of IP is possible via DNA analysis obtained by amniocentesis or
chorionic villus sampling.