Incontinentia Pigmenti

Bloch and Sulzberger, in 1926 and 1928, respectively

(Bloch 1926; Sulzberger 1928), were credited for

the first description of the clinical syndrome of

incontinentia pigmenti (IP), known as Bloch–

Sulzberger syndrome. It is a rare genodermatoses

occurring in approximately 1 in 50,000 newborns

(Aradhya et al. 2001).

Synonyms and Related Disorders

Bloch–Sulzberger Syndrome

Genetics/Basic Defects

1. Inheritance (Berlin et al. 2002).

a. X-linked dominant transmission, usually prena-

tally lethal in males, suggested by pedigree

analyses

b. A high affected female/affected male ratio

c. Instances of female-to-female transmission

d. 1:1:1 affected female/normal female/normal

male ratio in the offspring of an affected mother

e. Increased incidence of miscarriages in patients

with incontinentia pigmenti, presumably

representing affected male conceptuses that typ-

ically fail to survive past the second trimester

2. Female patients with IP mutations.

a. Dizygosity for the X chromosome

b. Skewed X-inactivation

i. Cells expressing the mutant X chromosome

are eliminated selectively around the time of

birth so that females with IP exhibit

extremely skewed X-inactivation, based on

the Lyon hypothesis (random inactivation of

one X chromosome in each cell of the female

at an early developmental stage, resulting in

an X-chromosomal mosaic for each female

with one X functioning in some of the cells

and the other X functioning in the rest of the

cells).

ii. Female heterozygous for an X-linked

incontinentia pigmenti gene: The pigmented

areas on the skin represent cell populations

in which the abnormal gene is active and the

areas of normal skin tissue in which the

normal gene is active.

iii. Highly variable phenotype explainable by

the chance variability in the number and

position of the cells carrying the active

incontinentia pigmenti gene.

3. The gene for IP: linked genetically to the factor VIII

gene in Xq28.

4. Molecular pathophysiology (Fryssira et al. 2010).

a. Attributed to mutations in the gene of nuclear

factor kappa B (NF-kB) essential modulator

(NEMO) currently known as IKBKG (inhibitor

of kappa light polypeptide gene enhancer in

B-cells, kinase gamma) (Smahi et al. 2000;

Jentarra et al. 2006; Fusco et al. 2008).

b. The IKBKG gene is located on chromosome X,

band q28. It spans 23 kb and consists of 10 exons.

c. An intrachromosomal rearrangement that deletes

exons 4–10 of the gene accounts for approxi-

mately 80% of new mutations.

d. The IKBKG gene encodes a protein which is

essential for the activation of NF-jB transcrip-

tion factor, which protects cells against tumor

necrosis factor–induced apoptosis.

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_133,# Springer Science+Business Media, LLC 2012

1175

e. The IKBKG gene also regulates the expression of

various cytokines, chemokines, and adhesion

molecules (Smahi et al. 2000; Berlin et al. 2002).

5. Mechanisms for occasional survival of affected

males (Berlin et al. 2002).

a. Presence of an extra X chromosome (47,XXY

Klinefelter syndrome)

b. Skewed X inactivation

c. Hypomorphic alleles

d. Mosaics for common mutations (somatic

mosaicism)

e. A parent with gonadal mosaicism

6. Anhidrotic ectodermal dysplasia with immunodefi-

ciency (EDA-ID):

a. A disorder allelic to incontinentia pigmenti but

with different phenotype due to various natures

of genetic mutations underlying the two

disorders

b. A rare X-linked recessive disorder affecting only

males

c. Caused by mutations in the NEMO gene

d. Possible family history of IP in boys with

EDA-ID

e. Presentation with severe recurrent infections

caused by common encapsulated bacterial path-

ogens, suggesting functional defects in the

immune response

f. Rare opportunistic diseases

i. Mycobacterial infections

ii. Cytomegaloviral infections

iii. Pneumocystis carinii pneumonitis

g. Immunologic studies

i. Normal or increased levels of B cells

ii. Normal T-cell counts

iii. Normal to low levels of IgG

iv. Elevated levels of either IgM or IgA

7. Eosinophil recruitment through eotaxin release by

activated keratinocytes.

8. Incontinentia nomenclature: The localization of the

gene for IP to Xq28, coupled with reports of chil-

dren with “incontinentia pigmenti” and X-autosome

translocations with breakpoints at Xp11, resulting

in a nomenclature differentiation of IP1 (sporadic)

and IP2 (familial). However, IP1 and IP2 designa-

tion should be abandoned.

a. IP1

i. Disorder applied to cases associated with

X-autosome translocations with Xp11

breakpoints and r(X) (Shastry 2000)

ii. Skin changes different from patients to

patients

iii. Serves no useful purpose either causally or

clinically

iv. More appropriately using descriptive phrase

“X-autosome translocation associated with

pigmentary abnormalities”

b. IP2: applied to cases of familial IP mapped to

Xq28

Clinical Features

1. Highly variable clinical presentations among

affected female family members (Berlin et al.

2002)

a. Attributed to lyonization in females, resulting

in functional mosaicism

b. Clonal expansion of the progenitor cell along

lines of embryonic development in that each

cell determines which X chromosome to

express during the first weeks of gestation

i. Manifesting along the curvilinear lines of

Blaschko in skin

ii. Percentage of progenitor cells that express

the mutated X chromosome reflecting the

extent of expression

iii. Mutation in a high percentage of ectoder-

mal cells in severe cases

2. Clinical expression among small number of live-

born male patients

a. Generally not severer than that in affected

females

b. Many male patients with disease expression

limited to cutaneous involvement of one or

two limbs

3. Cutaneous manifestations: most often the first

observed sign of IP and are present in nearly all

patients. They are classically subdivided into the

following four classic cutaneous stages:

a. Vesicular, vesiculobullous, or inflammatory

stage

i. Frequency: about 90% of cases

ii. Age of onset: within first 2 weeks of

life (92%), by 6 weeks of age (4%),

starting after the first year of life (several

cases)

iii. Age at resolution: blisters generally clear-

ing by 4 months, recurrence usually short-

1176 Incontinentia Pigmenti

lived and less severe than the original

eruption

iv. Clinical features: erythema, superficial vesi-

cles in linear distribution on torso and extrem-

ities (64%) and extremities alone (33%)

b. Verrucous (wart-like) stage

i. Frequency: about 70% of cases

ii. Age of onset: peak of onset between 2 and

6 weeks of age

iii. Age at resolution: clearance by 6 months

(80%)

iv. Clinical features: verrucous hyperkeratotic

papules and plaques almost exclusively

involving extremities

c. Hyperpigmented stage

i. Frequency: nearly all patients with IP (98%)

ii. Age of onset: 12–26 weeks of age

iii. Age at resolution: puberty

iv. Clinical features: whorls and streaks

of brown pigmentation following lines of

Blaschko (multiple lines on the human

body corresponding to the distribution of

linear nevi and dermatoses) on torso

and extremities (65%) and torso

alone (27%)

d. Atrophic (dermal scarring) stage

i. Frequency: 42%

ii. Age of onset: early teens to adulthood

iii. Age at resolution: permanent lesion

iv. Clinical features: pale, hairless, atrophic

patches, and/or hypopigmentation

4. Hair abnormalities (50%)

a. Vertex alopecia

i. The most common hair manifestation

ii. Most commonly mild and unnoticed

iii. Follows inflammation and vesiculation

iv. May be associated with scarring

b. Agenesis of eyebrows and eyelashes: infrequent

5. Nail abnormalities (7–40%)

a. Ridging, pitting, or nail disruption

i. Starting early childhood and involving all or

most of the fingernails and toenails

ii. Tend to regress and disappear with age

b. Subungual and periungual keratotic tumors

i. Appear at a later stage.

ii. Affect fingers more than toes.

iii. Continued growth results in pain, nail

dystrophy, and destruction of the

underlying bone of the terminal phalanx.

iv. Bone lytic lesions caused by pressure from

the overlying tumor.

6. Dental anomalies (>80%)

a. Partial adontia or adontia (43%)

b. Pegged and conical teeth (30%)

c. Late eruption of teeth (18%)

d. Enamel hypoplasia

7. Ophthalmologic anomalies (35%)

a. Blindness (7.5%)

b. Nonretinal manifestations

i. Strabismus (18–33%)

ii. Optic atrophy (4%)

iii. Cataracts (4%)

iv. Pseudoglioma (3.5%)

v. Microphthalmia (3%)

vi. Rare conjunctival pigmentation, iris hypo-

plasia, nystagmus, and uveitis

c. Retinal manifestations

i. Foveal hypoplasia

ii. Mottled or hypopigmented retinal pigment

epithelium

iii. Avascular retina

iv. Neovascularization

v. Vitreous hemorrhages

vi. Fibrovascular proliferation

vii. Retinal detachment (3%)

8. Neurologic deficits (30%)

a. Infantile spasms and seizure disorder (13%)

b. Mental retardation (12%)

c. Spastic paralysis (11%)

d. Motor retardation (7.5%)

e. Microcephalus (5%)

f. Infrequent manifestations

i. Cerebellar ataxia

ii. Congenital hearing loss

iii. Muscle paresis

iv. Aseptic encephalomyelitis

9. Other associated anomalies

a. Nipple anomalies

i. Supernumerary nipple

ii. Nipple hypoplasia

iii. Breast hypoplasia/aplasia

b. Oral anomalies

i. High arched palate

ii. Cleft lip/palate

c. Skeletal anomalies

i. Dwarfism

ii. Chondrodysplasias

iii. Short stature

Incontinentia Pigmenti 1177

iv. Spina bifida

v. Skull defects

vi. Club foot

d. Increased risk of serious and unusual infection

in some patients

e. Occasional hypohidrosis with increased rates

of bacterial skin infections: may be evidence

of the continuum between IP and the allelic

anhidrotic ectodermal dysplasia-immune

deficiency

f. Cardiac abnormalities

i. Tricuspid insufficiency

ii. Pulmonary vein-to-superior vena cava

shunt

10. Diagnostic criteria for incontinentia pigmenti

(Landy and Donnai 1993)

a. Negative family history (no evidence of IP in

a first-degree female relative): At least one

major criterion is necessary to make a firm

diagnosis of sporadic incontinentia pigmenti.

The minor criteria, if present, will support the

diagnosis. Because of their high incidence,

complete absence of minor criteria should

induce a degree of uncertainty.

i. Major criteria

a) Typical neonatal rash (erythema, vesi-

cles, eosinophilia)

b) Typical hyperpigmentation (mainly trunk,

Blaschko’s lines, fading in adolescence)

c) Linear, strophic, hairless lesions

ii. Minor criteria

a) Dental involvement

b) Alopecia

c) Woolly hair/abnormal nails

d) Retinal disease

b. Positive family history (evidence of IP in a first-

degree female relative of an affected female)

plus demonstration of any of the following fea-

tures, alone or in combination.

i. Suggestive history or evidence of typical rash

ii. Skin manifestation of IP

a) Hyperpigmentation

b) Scarring

c) Hairless streaks

d) Alopecia at vertex

iii. Anomalous dentition

iv. Woolly hair

v. Retinal disease

vi. Multiple male miscarriages

Diagnostic Investigations

1. Major histopathologic features from skin biopsy

samples (Berlin et al. 2002)

a. Vesicular, vesiculobullous, or inflammatory

stage

i. Spongiotic dermatitis

ii. Dermal and epidermal eosinophilia

iii. Eosinophil-filled vesicles

b. Verrucous stage

i. Papillomas

ii. Epidermal hyperplasia

iii. Hyperkeratosis

iv. Dyskeratotic cells

c. Hyperpigmented stage

i. Dermal melanophages

ii. Vascular changes in basal layer of epidermis

d. Atrophic stage

i. Loss of rete ridges

ii. Loss of dermal sweat coils

iii. Skin biopsy helpful for the diagnosis of IP at

late stage (IV) (Fraitag et al. 2009)

a) Slight atrophy and some scattered apo-

ptotic cells in the epidermis, epidermal

hypopigmentation, and reduced melano-

cyte number.

b) The dermis appeared thickened and

homogeneous and revealed a complete

absence of hair follicles (23/26) and

sweat glands (22/26).

c) There was no melanin incontinence or

inflammatory cells, and the elastic net-

work was normal.

2. CBC: marked peripheral blood leukocytosis and

eosinophilia

3. Abnormal immune system: not a consistent finding

4. CT/MRI imagings of the brain

a. Optic atrophy

b. Retinal vasculopathy

c. Hypoplasia of the corpus callosum

d. Ventriculomegaly

e. Periventricular white matter lesions

f. Ischemic strokes

g. Hemorrhagic necrosis

h. Porencephalic cyst

5. Magnetic resonance angiography/spectroscopy

for cerebral ischemia and a vaso-occlusive

phenomenon

1178 Incontinentia Pigmenti

6. Fluorescein angiography for retinal vascular

abnormalities

7. EEG for seizures

8. Chromosome analysis in male patients with IP

9. Molecular genetic testing: mutation detection for

the majority of families, facilitated by the high

frequency of specific deletion, using Southern blot-

ting, PCR amplification, or DNA sequencing

a. X-inactivation assay and Xq28 marker studies:

X-inactivation analysis is indicated wherever

a recombination event between Xq28 markers

and the disease locus is suspected. Absence of

recombination between the disease locus and

Xq28 loci suggests that mosaicism is responsible

for the discrepancy where Xq28 marker studies

are at odds with the clinical assessment.

b. Identification of the IKBKG (also known as

NEMO) gene mutation as a biological marker

for a molecular diagnosis of IP.

i. Deletion/duplication analysis

ii. Sequence analysis

iii. Carrier testing for the mother who has an

affected daughter with a known mutation

iv. Determine whether the miscarried or still-

born male fetus has IP

v. Prenatal testing of a fetus at risk

Genetic Counseling

1. Recurrence risk

a. Patient’s sib

i. Recurrence risk: <1%, provided that the

mother is not a carrier of the gene: a small

increased risk due to either a newmutation in

a second child or germ line mosaicism in

a parent

ii. Recurrence risk of 50% for sisters to be

affected when the mother is a carrier of the

gene

iii. Recurrence risk of 50% for brothers to be

affected (prenatally aborted fetuses or still-

borns) when the mother is a carrier of the

gene

b. Offspring of an affected female

i. Daughters: 50% affected; 50% normal

ii. Sons: 50% affected (prenatally aborted

fetuses or stillborns); 50% normal (all the

live-born sons will be normal)

c. Offspring of an affected male

i. All daughters affected

ii. All sons normal

2. Prenatal diagnosis possible if the disease-causing

mutation has been detected in the families at risk

a. Determination of the fetal sex by amniocentesis

or CVS.

b. An increased risk of miscarriage or stillborn for

an affected male fetus (fetal karyotype 46,XY).

c. If the fetal karyotype is 47,XXY: more severe IP

phenotype in males and of Klinefelter syndrome.

d. Molecular genetic testing of a female fetus: If the

fetal karyotype is 46,XX, there is 50% of fetuses

that are likely to be affected with IP.

e. Preimplantation genetic diagnosis may be avail-

able for families in which the disease-causing

mutation has been identified previously.

3. Management

a. Reduce the risk of secondary infection of blisters

b. Keep lesions dry

c. Avoid trauma to blisters

d. Dental care

e. Early photocoagulation or cryotherapy in cases

of retinal involvement

f. Intervention programs for learning disabilities

and developmental delay

g. Antiseizure medications for seizures

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Incontinentia Pigmenti 1181

a

b

Fig. 1 (a, b) Two girls with incontinentia pigmenti showing

classical hyperpigmentation on the trunk following Blaschko’s

lines

a

b

Fig. 2 (a, b) A girl with incontinentia pigmenti showing streaks

and whorls of brown pigmentation on the leg and trunk

1182 Incontinentia Pigmenti