This document describes the case of a newborn female (Sofia) referred for a diffuse vesiculo-bullous rash present from birth. Medical history of the mother and child are provided. Initial examination and testing of the rash are discussed. A skin biopsy is performed and histological examination confirms the diagnosis of incontinentia pigmenti, a rare X-linked genodermatosis. Key characteristics and stages of the disease are outlined.

1. S. Gianfaldoni, R. Gianfaldoni, A. Nannipieri – Department of
Dermatology, Pisa.
M. Giampietri, M. Ciantelli, L. Bartalena – Neonatology Intensive Care Unit,
Pisa.
A. Tognetti – Department of Pathology, Pisa.
T. Lotti –Department of Dermatology, Florence.
Barcelona 2 -5 November

2. Let’s talk about Sofia...

3. Sofia is a newborn female (15 days old).
She was referred to us with a diffuse
vesiculo-bullous rash. The rash was
present from birth.

4.  Grandmother: diabetes.
 Mother: single woman of 31 years. She had no
other children or miscarriages. She had a normal
mental and physical development. In childhood,
she suffered from varicella, rubeola, parotitis and
rubella.
No pathology except for epilepsy
(benzodiazepines).
No drugs.
No skin, nail or hair alteration. Also, she showed
no familiarity for any skin disease.
Sierologies negative for VDRL, HIV, HBV, HCV.
 Father: ?

5.  Born at term by spontaneous vaginal delivery
after 2,5 hours of ruptured membranes.
 The entire pregnancy took place regularly and
did not have any complication.
 SGA - Small for Gestational Age (2.48 Kg).
 From birth she had seizures.
The EEG showed a severely abnormal
pattern with frequent multi-focal spikes.
The head ultrasound showed a pattern of
immature SNC.

8. At first the neurologist thought that seizures
could derive from benzodiazepine’s
abstinence. Instead, seizures didn’t stop like
they didn’t depend by the mother’s therapy.

9.  Height: 48 cm.
 Weight: 2.6 kg (less than normal).
 Normal blood pressure
(70/40mmHg), pulse rate (120) and
breathing (40).
 The musculoskeletal system was normal
except for an hypoplastic mandible.
 No ocular alterations.
 No abdominal alterations.

10.  Clear, tense blister and bullae on
inflammatory bases. No pustules. No sign
of infection.
 Right arm, back of right hand, right and left
legs, left foot, right side of trunk.
 No scalp or face lesions.
 Blaschko’s lines.
 No symtoms.
 Negative Nikolsky test.

15.  No mucosal alteration.
 Hairs: less than normal, wiry and coarse
(“woolly hair”).
 Nails: dystrophy, onychorrhexis,
onycholysis.

16.  Blood test showed peripheral eosinophilia
(>20%).
 Normal c-reactive protein and
procalcitonin.
 No signs of infection (fever,
lymphadenopathy, etc...).

18.  Rare before 6 months
old.
 Clinical feature.
 No other signs of
inflammation (fever
and symptoms of
systemic toxicity).
 Tzanck smear.

19.  No familiarity for
Herpes Simplex.
 Clinical feature.
 No other signs of
inflammation (fever
and symptoms of
systemic toxicity).
 Tzanck smear.

20.  No other signs of
inflammation (fever
and symptoms of
systemic toxicity).
 Bacterial culture of the
lesions.

21.  Predominant in adult men.
 Itchy blisters and papules
on the extensor surfaces
(knees, elbows) and on
the sacral region. They
don’t follow the lines of
Blaschko.
 H.E.: abscess in the
papillar dermis.
 IF: deposition of granular
IgA at dermal papillae.

22.  Uncommon in childhood.
 Itchy clear, tense bullae
on inflammatory bases.
 Extremities.
 Symmetric.
 H.E.: subepidermal split.
 IF: linear deposits of IgG
and / or C3 along the
epidermal basement
membrane.

23.  Usually seen in the fifth
decade of life.
 Clear, tense bullae, quite
itchy. The bases aren’t
inflammatory.
 Mucosal lesions.
 Diffuse or localizd (e.g.
Axilla, groin, genitalis).
 Nikolsky sign is positive.
 H.E.: intraepidermal split.
 IF: deposits of IgG and /
or C3 along the plasma
membrane of
keratinocytes.

24.  Blistering lesion that
appear after light
trauma.
 H.E.: subepidermal
detachment.
 IF: IgG and C3 along
the dermal-epidermal
junction.

25.  Skin: vesicular and bollousus
rash, localized on the extremeties and on
the trunk (Blanschko’s lines).
 Hair: woolly hairs.
 Nails:
dystrophy, onychorrhexis, onycholysis.
 SNC: seizures.
 Skeletal: hypoplastic mandible.
 Peripheral eosinophilia.
We decide to do a skin biopsy to confirm our suspect.
The histological examination of the skin lesion
confirmed the diagnosis.

26. I.P. 10X:in the epidermis mild acanthosis, foci of eosinophilic spongiosis
and occasional dyskeratotic keratinocytes. The dermis shows an
infiltrate of lymphocytes, many eosinophils and nuclear dust derived
from eosinophilic karyorrhexis.

27. I.P. 10X: the dermis shows an infiltrate of lymphocytes, many eosinophils
and nuclear dust derived from eosinophilic karyorrhexis.

28.  Because the spontaneous improvement
and resolution of skin lesions, we didn’t
prescribe topical or systemic steroids.
 We prescribed only an antibiotic therapy to
avoid secondary infections of the lesions.

29. Two weeks
later....

37.  The vesiculo-bullous rash was
disappeared.
 Linear warty lesions.
 Back of right hand and of left foot (fingers
and toes), right and left legs.
 No lesions on the trunk.
 Woolly hairs.
 Nail’s distrophy. Onychorrhexis,
onycholysis.

38. X-linked genodermatosis. It is a systemic disease
that involves tissue of ectodermic and mesodermic
origin, including cutaneous tissue, teeth, eyes and
the central nervous system, amongst other
organs.

39.  The disease has been reported by Bloch in
1926, and Sulzberger in 1928.
 The name “incontinentia pigmenti” is
related to the histological characteristics of
the lesions during the third, pigmentary
stage, of the disease. It is melanin
incontinence by melanocytes in the basal
epidermal layer and its presence in the
superficial dermis.

40.  Prevalence is unknow. More than 700 cases have
been reported in the world literature up-to-date.
 IP occurs in approximately 1 in 50.000 newborns1
or in 1 in 10.000 of female newborns.
 The disease is predominant in women (male-female
ratio 1:37).
 Less than 3% of cases are male and derives by
other genetical disorder, not completely understood.
 Most cases have been described in white persons.
Also other races (e.g. Korean, brasilian, cinese) are
affected.
 About 50% of the IP cases have a positive family
history.

41.  IP is a hereditary, X-linked dominant
disorder.
 It has high penetrance but expressivity
highly variable.
 IP is a single gene disorder, caused by
mutations in the NEMO/IKKγ/IKBKG gene.

42.  NEMO is a 23kb gene, composed of 10 exons. It is
located on Xq28.
 NEMO is the essential modulator of NF-kB.
 NF-Kb is a transcriptor factor involved in immune and
inflammatory responces and in protecting cells from
tumor necrosis factor induced apoptosis. Normally, NF-
kB is described in the cellular cytoplasm. It is inactivated
by the linking of a protein IkB.
 Flogistic stimulant (like TNF, IL1, LPS, etc) activate the
Ikk complex. The Ikk kinase complex is made of two
kinases (Ikkα and Ikkβ) and a regulatory subunit, NEMO.
 The Ikk complex phosphorize the IkB protein, which is
degraded. NF-kB comes in the nucleus and starts the
inflammatory responces.

43. Ikkγ
Ikkα Ikkβ
Ik
NF-kB B
Nucleus

44. TN
IL- F
1
Ikkγ
Ikkα Ikkβ
Ik
NF-kB B
NF-kB
Nucleus

45. Other phenotypes associated with NEMO
mutation:
EDA-ID (“anhidrotic ectodermal dysplasia and
immunodeficiency”)
OL-EDA-ID (“osteopetrosis and lymphedema in
EAD-ID”)

46.  Deletion of exons 4 through 10 (70-80% of IP
patients).
 Other alteration in NEMO: small duplications,
substitutions and deletions.
 In male carrying a NEMO mutation this is linked to
embryonic lethality.
 Female survives for the X chromosome
inactivation (“lyonization”), which occur during
early embryogenesis.
 Many infant boys with the disease had evidence of
Klinefelter’s syndrome (47,XXY karyotype).
Affected surviving male have also been found with
hypomorphic alleles or somatic mosaicism for the
common IKBKG deletion.

47.  Also inflammatory reactions and epidermal eosinophil
recruitment in the initial stage of IP seems to be
important in the disorder.
 The exact mechanism of epidermal eosinophil
accumulation has not been yet determined.
 Eotaxin is an eosinophil-selective chemokine, which is
producted by specific leucocytes (including
eosinophils, macrophages, Tcells) and some structural
cells (including endothelial cells, fibroblasts and
epithelial cells).
 Eotaxin is strongly expressed in the epidermis of IP
lesional skin. Probably eotaxin is producted during the
inflammatory responces due to the activation of NF-kB.

48. The clinical presentation of IP vary
considerably even among family members.
They range from subtle cutaneous and
dental involvement to a complex
syndrome, sometimes deadly.

49.  Skin manifestations are the
most common.
 Characteristic skin lesions
evolve through four stages.
 The skin abnormalities occur
along lines of embryonic and
fetal skin development, know as
Blaschko’s lines. Blaschko’s
lines correspond with cell
migration or growth pathways
that are established during
embryogenesis.

50.  STAGE 1 – BULLOUS STAGE
 STAGE 2 – VERRUCOUS STAGE
 STAGE 3 - HYPERPIGMENTATION
STAGE
 STAGE 4 - ATRETIC STAGE

51.  Is present in 90% of the patients at birth or within the first two weeks
of life. It can occur in utero and don’t progress after birth.
 Clear, tense bullae on inflammatory bases. Sometimes the eruptions
may appear infectious. The bullae are accompanied or followed by
smooth red nodules or plaques.
 The lesions tend to follow the lines of Blaschko. The lesions are
tipically described on the extremities (linear pattner) and on the trunk
(linear or circumferential pattern). The face is usually spared,
although scalp lesions are quite common.
 The stage 1 rash generally disappears by age 18 months.
Recurrence of stage 1 lesions can be observed.
 Histopathologically, stage 1 is characterized by eosinophilic
spongiosis, intraepidermal vesicles. The dermis shows non-specific
inflammatory changes with a a cellular infiltrate, including numerous
eosinophils.

52.  Usually, stage 2 follows between the second and sixth weeks of life.
It persists for a few months and in 80% of cases fades by the age of
six months.
 It is characterized by a hypertrophic, wart-like rash, similar to the first
stage pattern.
 Histopathologically, the lichenoid papules are characterized by
dyskeratotic keratinocytes, hyperkeratosis, acanthosis and
papillomatosis. Also macrophages laden with melanin are present in
the upper dermis. We can also describe inflammation of epidermis
and dermis (epidermal spongiosis, cellular infiltrate including
numerous eosinophils).

53.  Most characteristic stage for IP.
 Usually it begins between age six months and one
year, and persist into adulthood. Spontaneous
improvement and resolution of skin lesions is general
the rule.
 Brownish linear and whorled streaks that follow the
Blaschko’s lines (blue-grey or slate to brown).
 The bizarre splashed or Chinese figure distribution are
diagnostic. Sometimes we also describe linear or
macular teleangiectasias.
 Histopathologically, stage 3 is characterized by melanin
incontinence by melanocytes in the basal epidermal
layer and its presence in the superficial dermis.

54.  About 14% of patients exhibits a fourth
stage.
 Hypopigmentation in the areas of the
previous hyperpigmentation, with atrophy.
 Histopathologically, stage 4 is
characterized by epidermal atrophy and
decreased, normal or small melanocytes.
Sometimes, skin appendages are absent.

55.  The onset and duration of each stage vary
among individuals, and not all individuals
experience all four stages. Stage 1 and 3
are more common than stage 2 and 4.
 Different skin manifestations: palmo-plantar
hyperhidrosis, port wine stain, cleft lip and
palate, abnormalities of mammary tissue
(aplasia of the breast, supernumerary
nipples ).

56. HAIR NAILS
 40% of patients .
 Scarring alopecia (28-38%).  First three digits of the
 Thin hair . hands.
 Woolly hair (lusterless, wiry  Multiple digits on multiple
and coarse). limbs.
 Most common nail
alterations:
onychodystrophy,
onychogryphosis, pitting,
yellow discoloration.
 Subungeal and periungueal
keratotic tumors may appear
at the later stage.

58.  80% of all IP patients.
 Both the deciduous and permanent dentition may
be affected.
 The most common dental alterations are: delayed
dentition (18%), partial anodontia (43%),
hypodontia (40%) and abnormally shaped teeth
(e.g. cone or peg-shaped teeth or accessory
cusps) (30%).
 Dental abnormalities if not treated adequately, will
lead to problems in masticatory and occlusal
function, and probably psychosocial problems due
to a compromised esthetic appearance.

59.  40% of the cases.
 Asymmetric involvement is the most common.
 The defects include strabismus, cataract,
conjuntival pigmentosa uveitis, optic nerve
atrophy, retinal vascular abnormalities, blue
sclera, exudative chorioretinitis, retinal
glioma.
 In most of patients with ocular defects,
prognosis is not good: many of them become
blind.

60.  25% of IP cases.
 Seizures are the most common symptoms
(prognostic indicator).
 Other neurologic symptoms include:
spastic or paralytic
quadriplegia, hemiparesis, cerebral
atrophy, microcephaly and
encephalopathy.
 The majority of individual with IP are
intellectually normal. The incidence of
mental retardation is about 25-35%.

61.  Have been observed,
including
hemivertebra,
hemiatrophy,
syndactily, congenital
dislocation of the hip,
club foot, dwarfism,
scoliosis,
supernumerary ribs.

62.  Uncommon.
 Atrialseptal defects, acyanotic tetralogy of
Fallot, ventricular endomyocardial fibrosis,
tricuspid insufficiency, unilateral acheiria
and primary pulmonary hypertension.

63.  Common in IP.
 They include functional abnormalities of
neutrophils and lymphocytes and defects
in polymorphonuclear chemotaxis. Also
eosinophilia up to 50% in the peripheral
blood is usual in first inflammatory stage of
IP.

64.  No strict diagnostic criteria for IP exist.
 The diagnosis is mainly clinical.
 Family history consistent with X-linked
inheritance or a history of multiple
miscarriages also supports the diagnosis.

65. MAJOR CRITERIA (skin lesions that MINOR CRITERIA
occur in stages from infancy to
adulthood)
Erythema followed by blister, in a Teeth: hypodontia, anodontia,
linear distribution – stage 1 microdontia, abnormally shaped teeth
Hyperpigmented streaks and whorls Hair: alopecia, woolly hair
that respect Blaschko’s lines – stage 3
Pale, hairless, atrophic linear streaks Nails: onychodystrophy,
or patches – stage 4 onychogryphosis, pitting, yellow
discoloration.
Ocular alterations (retinal
neovascularization)
The clinical diagnosis of IP can be made if at least one of the
major criteria is present. The presence of minor criteria supports
the diagnosis; the complete absence of minor criteria should
raise doubt regarding the diagnosis.

66.  Peripheral eosinophilia.
 Histological examination of a skin biopsy.
 Immunofluorescent antibody/antigen mapping
(negative).
 Molecular genetic testing (NEMO mutation).
 X-chromosome inactivation studies (female
with IP have skewed X-chromosome
inactivation in which the X-chromosome with
the mutant IKBKG allele is preferentially
inactivated).
Prenatal diagnosis: analysis of DNA extracted from fetal cells
obtained by amniocentesis (15 to 18 weeks’ gestation) or
chorionic villus sampling (10 to 12 weeks’ gestation).

67. STAGE OF IP DIFFERENTIAL DIAGNOSIS
STAGE 1 Infectious: bullous impetigo, herpes
simplex, varicella.
Immune-mediated: dermatitis
herpetiformis, epidermolysis bullosa
acquisita, bullous systemic lupus
erythematosus, linear IgA bullous
dermatosis, bullous pemphigoid,
pemphigus vulgaris.
STAGE 2 Verrucae vulgaris, linear epidermal
nevi, molluscum contagiosum.
STAGE 3 Skin hyperpigmentation,
hypomelanosis of Ito.
STAGE 4 Vitiligo, piebaldism and other skin
hypopigmentation, scars.

68. 1. Physical examination with particular emphasis on
the skin, hair, nails, neurologic system.
2. Ophthalmological examination.
3. Dental examination (?).
4. EEG and MRI if neurological abnormalities are
present.
5. Magnetic resonance angiography if neurological
deficits are consistent with a stroke like pattern.
6. Developmental screening, with further evaluation
if significant delay are identified.

69.  The prognosis is generally good and
depends on extracutaneous
manifestations.
 For persons without significant neonatal or
infantile complications, life expectancy is
considered to be normal.
 Women with IP have a higher than usual
risk of pregnancy loss, presumably related
to low viability of male fetuses.

70. Because IP is a systemic disorder, a multidisciplinary approach to
management is crucial.
A complete neurologic examination is
warrented for all IP infants.
 Regular visits to a pediatric ophthalmologist is
essential during the first year of life. Laser
photocoagulation and vascular endothelial
growth factor inhibitor seem to be good
treatments for retinal vascular abnormalities.
 Concerning teeth, referral for radiologic
evaluation and dental intervention by the age
of two years is appropriate.

71.  Management in the newborn period is aimed
at reducing the risk of infection of blisters
using standard medical management.
 Spontaneous improvement and resolution of
skin lesions is general the rule.
 Topical and systemic steroids have been
prescribed to limit the stage 1 and 2 rashes.
 The use of laser treatment of
hyperpigmentation should be discouraged
because it has been reported to trigger an
extensive vesciculobullous eruption.