CUTANEOUS MOSAICISM: A

MOLECULAR AND CLINICAL POINT OF

VIEWBy

Lamia ElgarhyAssistant lecturer

INTRODUCTION

Since Blaschko first reported the

patterns of epidermal nevi in 1901,

dermatologists have recognized that

many inherited and sporadic skin

conditions appear in distinct cutaneous

patterns

The concept of genetic mosaicism has

been used to explain these patterns.

LINES OF BLASCHKO

INTRODUCTION

Genetic mosaicism defined as two or more cell

populations with distinct karyotypes or

genotypes in one individual.

At the same time, Montgomery proposed the

theory that the patterned lines on the skin

represented the dorsoventral outgrowth, as

embryonic cells follow a path of migration from

the neural crest in the developing embryo.

INTRODUCTION

For mutations that occur early in

embryologic development, the condition

may be apparent over a broader body

surface area;

whereas later mutations will be

apparent in smaller, more confined

anatomic regions.

PATTERNS OF CUTANEOUS MOSAICISM

•Ia:narrow lines of Blaschko.

•Ib:broad lines of Blaschko

Type I•chec

kerboard

Type II

•phylloidType

III

•large patches without midline separation

Type IV

•lateralization

Type V

LINES OF BLASCHKO

TYPE IA:IA:NARROW LINES OF BLASCHKO

Demonstration of the narrow lines of Blaschko on the neck and chest (A) and abdomen (B), showing sharp midline demarcation in a child with porokeratotic eccrine ostial and dermal duct nevus.

•segmental pigmentation disorder

• McCune-Albright syndrome

Type Ib

•Becker’s nevus

•congenital melanocytic nevi

•segmental neurofibromatosis

Type II

•leaf-like or oblong patterns

•hypopigmented patches in trisomy

Type III

•bathing-trunk distribution of giant congenital melanocytic nevi

Type IV

•the type of nevus seen in CHILD syndrome

Type V

CELL MIGRATION

Keratinocytes

Melanocytes

Angioblasts

A- MELANOCYTES Melanoblasts are neural crest-derived cells that

migrate via the mesenchyme as single cells

during embryogenesis.

10-weeks gestation, the melanocytes are located

diffusely in the dermis.

Later, some melanocytes undergo a presumed

programmed cell death, while others continue the

migration to the epidermis and basal layer of the

hair matrix in the outer root sheath of the hair

follicles.

B- KERATINOCYTES

Dorsoventral migration pattern.

Later curving in lines, which likely

explains the appearance of the whorls

and streaks along the lines of Blaschko

(type 1), such as in incontinentia

pigmenti.

The lines of Blaschko can also be seen

in the oral mucosa, the bone, and the

eye.

C- ANGIOBLASTS

originate in the central body axis with a

lateral migration.

Vascular birthmarks commonly present in

a segmental or dermatomal pattern, and

are therefore possibly caused by a

postzygotic mutation, leading to abnormal

migration or formation of the vasculature

in a localized area. (not yet been proven)

CURRENT AND FUTURE Historically, conventional cytogenetic analysis has

been the most common tool for screening for

chromosomal anomalies; however, this technique is

time consuming, labor intensive, and requires cell

culture.

Array comparative genomic hybridization (CGH) is

emerging as a new technique for high-resolution,

genome-wide scanning in congenital anomaly

syndromes. This technique has also been referred

to as chromosomal microarray analysis.

MOSAICISM

Gonadal Gonosomal

GONADAL MOSAICISM

in the germ-line tissues only

autosomal dominant

proven in the sperm of fathers

Examples:

Cornelia de Lange, Pallister-Hall,

Conradi-Hu¨ nermann-Happle syndrome

hereditary angioedema

GONADAL MOSAICISMCornelia de Lange syndromeis characterized by: distinctive facial features, short stature, hirsutism and synophrys, long eyelashes, and limb reduction defects. The disorder is caused by mutations in

the Nipped-B-like (NIPBL) gene

GONOSOMAL MOSAICISM

mutations are present in both somatic

tissue and in the gonadal tissue.

This has been implicated in cases of

segmental presentations in the parent

and subsequent full-blown expression in

the affected offspring.

GONOSOMAL MOSAICISM

Examples have

included:

segmental

neurofibromatosis

(NF) type 1 in a

parent with full

expression of NF1

in the offspring.

GONOSOMAL MOSAICISM

The classic example

is an individual with

epidermal nevi of the

epidermolytic

hyperkeratosis-type

who has an offspring

with generalized

epidermolytic

hyperkeratosis.

Mechanism Definition

Postzygotic (somatic) mutation

A mutation or chromosomal replication error that occursafter fertilization.

Lyonization In females, one X-chromosome (either the maternal or thepaternal X chromosome), is randomly inactivated in earlyembryologic development; that change is carried on in allfuture cell divisions

Chimerism When an organism is composed of two or more geneticallydistinct cell lines with completely different genetic makeup. This may occur after bone marrow or organ transplantor maternal-fetal transfusion.

Revertant mosaicism Spontaneous correction of an inherited mutation.

MOLECULAR MECHANISMS

Epigenetic mosaicism

Chimerism

Segmental

Twin-spotting

Chromosomal structural abnormaliti

es

RevertantFunctional

SEGMENTAL MOSAICISM

Segmental

Postzygotic

Loss of heterozygosity

SEGMENTAL MOSAICISMType 1:

o segmental changes occur as a

postzygotic mutation.

o the cutaneous changes are seen only in

a localized segment, while the

remaining skin is unaffected.

SEGMENTAL MOSAICISMType 2 loss of heterozygosity(LOH)

a generalized phenotype is apparent with an

exaggerated expression localized to one

region.

Examples :

neurofibromatosis, Hailey-Hailey disease, and

Darier’s disease in individuals with typical

lesions and a superimposed segmental

presentation

Mechanism Definition

Mitotic recombination The formation of new combinations of alleles because of the exchange of a segment of DNA by crossing over betweenhomologous chromosomes.

Gene conversion One allele converts the mutated sequence of the other allele tothe wild-type sequence, possibly by nonreciprocal exchange

Point mutation A change in a single base pair

Deletion Loss of a portion of sequence of DNA; may range from onebase pair to a large portion of the chromosome.

Mitotic nondisjunction Failure of the chromosomes to separate properly during meiosisor mitosis; the result is that one daughter cell receives bothchromatids and the other receives neither chromatid

FUNCTIONAL MOSAICISM

occurs in females as a result of X-

inactivation.

The mechanism for inactivation is via

the X-inactivation site, located at Xq13.2

containing the XIST gene.

REVERTANT MOSAICISM often demonstrated in autosomal recessive conditions.

Example:non-Herlitz junctional epidermolysis bullosa

(EB) in which mutations in the type XVII collagen gene,

COL17A1.

Mechanism:

it is proposed that one allele converts the mutated

sequence of the other allele to the wild-type sequence,

possibly by nonreciprocal exchange.

Recently,It is hypothesized that this may have been

because of the expansion of clonal epidermal stem cells.

CHROMOSOMAL NUMERIC OR STRUCTURAL ABNORMALITIESExamples:

structural abnormalities, such as:

ring chromosomes,

deletions, or

duplications,

numeric abnormalities, such as:

in mosaic trisomy 21.

Chromosomal mosaicism results from events that take

place after fertilization and result in failure of the

chromosomes to separate properly during cell

division;this is also known as nondisjunction.

CHIMERISM

Blood chimerism can result from twin-

twin transfusion in dizygotic twins

Chimerism can occur from a transfusion

between a mother and her fetus as well

EPIGENETIC MOSAICISM the total number of genes in the human genome was

less than expected: approximately 20,000 to 25,000

genes.

Epigenetic regulation refers to a variety of heritable

mechanisms for altering gene expression

The epigenetic factors that control changes in gene

expression can be heritable and in some cases are

transmitted to the next generation. In other cases,

the epigenetic controls may only be effective during

embryogenesis.

Imprinting’’ is the term used to describe the

situation in which gene expression is

dependent on the sex of the transmitting

parent.

Examples of diseases that are

influenced by imprinting include Albright

syndrome, Beckwith-Wiedemann

syndrome,Prader-Willi syndrome, and

Angelman syndrome

TWIN-SPOTTING

It is proposed as a potential mechanism

for the development of coexisting

birthmarks, such as nevus simplex with

adjacent Mongolian spots or pigmentary

nevi.

CLINICAL EXAMPLES

Autosomal dominant conditions

X-linked-dominantmutations: lethal in thehemizygous male

Autosomal lethalmutations survivingby mosaicism(gene known)

Sporadic conditions:presumed autosomallethal, but genetic basisnot yet determined

Revertant mosaicism

Polygenic withsuperimposedsegmental presentation

Incontinentia pigmenti(NEMO gene) Conradi-Hunermann-Happle syndrome(EBP gene)Goltz syndrome(PORCN gene)

CHILD syndrome(NSDHL gene)

McCune-Albright(GNAS gene)

Encephalo-cerebrocutaneouslipomatosis

Proteus syndrome

Epidermolysis bullosa(LAMB3, KRT14, andCOL17A1 genes)

Linear psoriasisLinear lichen planusLinear systemic lupusErythematosus Linear pemphigusvulgaris

SEGMENTAL NEUROFIBROMATOSIS

Type I:The proposed mechanism

for

development of segmental NF1 is

a postzygotic somatic mutation in

the NF1

gene.

Type II: typical generalized skin

lesions

with a superimposed segmental

manifestation

Axillary freckling and cafe´-au-laitmacules in the segmental pattern on the axilla and chestof a toddler with segmental neurofibromatosis

SEGMENTAL DARIER’S DISEASE The molecular basis of Darier’s disease is a

causative mutation in the ATPase, calcium

dependent gene (ATP2A2)

In segmental Darier’s disease, the warty

papules are localized in a Blaschko-linear

pattern in one region of the body.

ATP2A2 mutations were identified in the

lesional skin, but not in the blood or unaffected

skin, confirming a mosaic mutation

CLINICAL EXAMPLESAutosomal lethal

mutations surviving by mosaicism

MCCUNE-ALBRIGHT SYNDROME caused by sporadic postzygotic-activating mutations

in guanine nucleotide-binding protein, alpha-

stimulating activity polypeptide 1, (GNAS1 gene)

MCCUNE-ALBRIGHT SYNDROME The clinical features:

large, segmental, unilateral cafe´-au-lait patches,

which in some cases have been described as

following the broad lines of Blaschko and in other

cases have been described as having a ‘‘coast of

Maine’’ appearance

polyostotic fibrous dysplasia

and endocrine abnormalities, including

precocious puberty.

X-LINKED CONDITIONS X-linked dominant conditions occur predominantly in

females who are presumed to survive because of the

functional mosaicism created by X-inactivation.

X-linked dominant conditions are generally lethal in

hemizygous males.

Affected males have been reported for each of these

conditions; some were shown to have Kleinfelter

syndrome (XXY), while others were presumed to

survive because of postzygotic mutations leading to

somatic mosaicism

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME X-linked dominant disorder

affecting both mesodermal

and ectodermal structures,

including the skin, eyes, teeth,

and digits

atrophic, hypopigmented,

linear streaks with

telangiectasia and punctuate

cribiform scarring, as well as

subcutaneous fat herniations

into the dermis along the lines

of Blaschko.

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

Raspberry-like papillomas

frequently appear in the

perioral and anogenital

regions.

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

The classic radiologic

features are

osteopathia striata

(noted in the mid-

portion of the lower

extremities),

limb reduction

abnormalities, and

syndactyly.

CONRADI-HUNERMANN-HAPPLE SYNDROME (X-LINKED CHONDRODYSPLASIA PUNCTATA)

in the neonate presented

after birth by erythroderma

and linear hyperkeratosis

and psoriasiform scale.

later in childhood As the

erythroderma resolves,

linear streaks with fine scale

and ichthyosis along

Blaschko’s lines become

apparent

CONRADI-HUNERMANN-HAPPLE SYNDROME (X-LINKED CHONDRODYSPLASIA PUNCTATA)

Scarring alopecia

on the scalp along

Blaschko’s lines is

also common.

Cataracts may

develop

CONRADI-HUNERMANN-HAPPLE SYNDROME (X-LINKED CHONDRODYSPLASIA PUNCTATA)

The extracutaneous

features include

limb reduction,

distinctive facial

features with

asymmetry, frontal

bossing, and saddle

nose.

INCONTINENTIA PIGMENTI Incontinentia pigmenti (IP) is an X-linked

dominant disorder affecting the skin, teeth, hair,

nails, and eyes caused by amorphic mutations in

the NEMO (necrosis factor kappaB or NFkB

essential modulator) gene in which the altered

gene product lacks the molecular function of the

wild-type gene.

The Blaschko-linear pattern of the cutaneous

lesions reflects functional mosaicism because of

Lyonization.

INCONTINENTIA PIGMENTI

Females are able to survive because of

Lyonization.

In boys the mutation is presumed to be

lethal because of expression of the

mutant allele in all cells.

Males who survive are presumed to

have had postzygotic mutations or have

Kleinfelter syndrome (XXY)

INCONTINENTIA PIGMENTI

INCONTINENTIA PIGMENTI

The cutaneous lesions of IP evolve through four

distinct phases:

First: vesiculobullous phase

Second : verrucous lesions

Third: hyperpigmented streaks and whorls

along the lines of Blaschko

Fourth: subtle hypopigmented atrophic

streaks with absent eccrine glands and hair

follicles

INCONTINENTIA PIGMENTI

The teeth: conical and peg-shaped

nail dystrophy.

The characteristic eye findings :retinal

vascular anomalies and optic atrophy.

neurologic : developmental delay and

seizures.

ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY

It is due to hypomorphic mutations in the

NEMO gene which result in an altered gene

product that possesses a reduced level of

activity, or in which the wild-type gene product

is expressed at a reduced level.

(ED-ID) is an X-linked recessive disorder; the

phenotype occurs in hemizygous males.

Females are spared because they have one X-

chromosome with the wild-type gene.

ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY

The features of ED-ID are combined

humoral and cell-mediated

immunodeficiency and variable features

of ectodermal dysplasia, including

reduced sweating and dental anomalies.

X-LINKED RECESSIVE HYPOHIDROTIC ECTODERMAL DYSPLASIA Occurs in hemizygous males by mutations in the

ectodysplasin A gene

Features:

a characteristic facial phenotype with full lips and

periorbital ridging,

thin, sparse, blond hair, lack of sweating,

and abnormal teeth.

The clinical features in carrier females may include

patchy absence of vellus hair and stripes of hypotrichosis

on the limbs and back, and mild to moderate

hypotrichosis of the scalp hair.

X-LINKED RECESSIVE HYPOHIDROTIC ECTODERMAL DYSPLASIA

X-LINKED RECESSIVE HYPOHIDROTIC ECTODERMAL DYSPLASIA

The carrier status in females may be

difficult to diagnose clinically.

Interestingly, the functional mosaicism

in these female carriers can be

demonstrated using a starch iodine test,

which reveals a lack of sweating along

the lines of Blaschko

CHROMOSOMAL MOSAICISM

It is based on pigmentary alteration

along the lines of Blaschko in children

with developmental delay and additional

congenital anomalies.

chromosomal abnormalities reported,

include structural abnormalities,

balanced translocations, and polyploidy.

CHROMOSOMAL MOSAICISM

In some cases, the chromosomal

abnormalities were reported in all cells

and in other cases the changes were

reported as mosaic (affecting only a

subset of cells).

OTHER SPORADIC CONDITIONS

PROTEUS SYNDROME is named after the Greek sea-god, known

for the ability to assume many different shapes.

The general criteria for the diagnosis of Proteus syndrome include:

mosaic distribution of the lesions, sporadic occurrence, and progressive course. a cerebriform connective tissue nevus on

the soles of the feet is present, the diagnosis of Proteus syndrome can be made

PROTEUS SYNDROME If not, then additional diagnostic

criteria include : asymmetric, disproportionate

overgrowth of the limbs or viscera, and hyperostosis.

Specific tumors can also be seen, including bilateral ovarian cystadenoma or parotid monomorphic adenoma.

Finally, dysregulation of adipose tissue, vascular malformations, and lung cysts may be additional features.

PROTEUS SYNDROME Surgical intervention is not recommended

unless ‘‘absolutely necessary,’’ because the

complication rate is high [62]. Deep vein

thrombosis is one of the most common causes

of death.

it is theorized that it is caused by mutations

that would be lethal in a nonmosaic state; in

other words, the embryo would not survive if

the mutation was present in all cells

SEGMENTAL PIGMENTATION DISORDER (PATTERNED DYSPIGMENTATION)

It is pigmentary

changes along the

lines of Blaschko or

large segmental cafe

´-au-lait patches do

not have associated

congenital anomalies

or other systemic

associations.

SEGMENTAL MANIFESTATIONS OF POLYGENIC AND INFLAMMATORY SKIN DISORDERS

Several inflammatory and polygenic

conditions have been reported with

linear or segmental presentations.

Generally, these conditions present with

a more severe segment overlying a

milder background of generalized

involvement.

SEGMENTAL MANIFESTATIONS OF POLYGENIC AND INFLAMMATORY SKIN DISORDERS

examples in the literature include linear

psoriasis, linear lichen planus, linear

systemic lupus erythematosus, linear

pemphigus vulgaris, linear atopic

dermatitis, linear graft-versus-host

disease, segmental granuloma annulare,

and linear fixed-drug eruptions