The Genetics of
Ichthyosis
Sherri J. Bale, PhD, FACMG
Clinical Director, GeneDx
FIRST Family Conference
Orlando, FL - June 27, 2010
What we’re going to talk
about
A primer on how ichthyosis
genetically occurs, the chances of
passing it along and what genetic
tests are available and how they are
administered
How many different
ichthyoses are there?

> 20 disorders fit the definition of
ichthyosis

> 10 other related disorders with more
localized scaling/hyperkeratosis
How are ichthyoses
classified?

Clinical features



Non-syndromic ichthyoses
Syndromic ichthyoses
Related disorders

Inheritance pattern

Gene defects

Etiology
Enzyme deficiencies
 Structural protein defects
 Regulatory protein defects
 Other

Genetics 101

Chromosomes – structures inside the nucleus
(command center) of the cell.

On the chromosomes, we carry genes

Genes are made up of a chemical called DNA

Chromosomes, and thus genes, are passed from
parent to child following “rules of inheritance”
[Mendel’s laws]
Genetics 101
Human Chromosomes
Types of Inheritance

X-linked
Recessive
 Dominant (rare)


Autosomal
Recessive
 Dominant

Steroid-Sulfatase
Deficiency


X-linked recessive
Incidence 1:6000 males

Primary features
Onset between 1 and 3 weeks of age
 Dark scale, tightly adherent
 Most prominent on flexure surfaces
(aka “Dirty neck” ichthyosis)
 Asymptomatic corneal opacities (10-50%)
 Cryptorchism (12-25%), increased risk of
testicular cancer
 The disease does not improve with age

Steroid-Sulfatase Deficiency
• Diagnostic
•  plasma cholesterol sulfate levels
• Assay to directly measure activity of steroid
sulfatase is rarely done
• Decreased placental sulfatase causes delayed
onset/progression of labor in affected male
fetuses
• Genetics
• STS gene on chromosome Xp22.32
• 90% of affected males have large intragenic
deletions, or contiguous gene deletions
Autosomal Dominant Ichthyoses
Ichthyosis
Gene
Epidermolytic hyperkeratosis
Epidermolysis Bullosa Siemens
Pachyonychia congenita I,II
KRT1; KRT10
KRT2e
KRT6a,b,
KRT16,
KRT17
KRT9
many genes
GJB2 (GJB6)
GJB3, GJB4
Epidermolytic PPK
Non-epidermolytic PPK
Keratitis-Ichth-Deafness (KID)
Erythrokeratoderma variabilis
Epidermolytic
Hyperkeratosis

Autosomal Dominant
(1/2 the cases are due to new mutations)

Incidence 1:200,000-1:300,000

Primary Features
Neonatal blistering, erosions and denuded skin
 Progressive Hyperkeratosis, esp. of the flexures
 Variable palm/sole involvement

Epidermolytic Hyperkeratosis
• Genetics
• Due to mutation in keratin-1 (KRT1) or keratin10 (KRT10) gene
• >40 different mutations, most are missense
changes
• >80% cluster at hot spots at the beginning or
end of the gene
•In 30% of all EHK patients mutations occur at
Arg156 in KRT10
How can you say its autosomal
dominant? I’m the only person in my
family with this disorder!
?
Germline Mutation
Ovaries
Testes
Sperm
Mutation
Egg cell
Mutation
Germline Mutation
Conception
Mutation
Disease
I have a been diagnosed with an
‘Epidermal Nevus’. What is it and how
does it come about?
?
‘Epidermal Nevus’
= Skin Mosaicism for Mutation
Gametes Zygote
Mutation
Post-zygotic
mutation
Two cell lineages
Cell Migration
Mosaic
Mosaicism
• Due to DNA Mutation that occurs during mitosis of a
single cell at early stages of fetal development
“post-zygotic mutation”
• All descendent cells will carry the mutation, other cells are
normal
• Gives rise to two (or more) genetically distinct cell lines
derived from a single zygote
• Mosaicism can affect somatic and/or germline tissues
• Generally only parts of the organism are affected
I have an ‘Epidermal Nevus’. Should I
be worried about my children?
?
• If germline is affected,
mutation can be
transmitted to the
offspring resulting in
full-blown disease
What is my risk of having an affected
child?
?
• Greater than the
population risk for a
new mutation
• Depends on what
percentage of germ cells
harbor mutation
• Rule of thumb:
• Small nevus-small risk
• Large nevus on both
sides of the body-high risk
Autosomal Recessive
Ichthyoses
Ichthyosis
Harlequin ichthyosis
Lamellar ichthyosis
CIE
Sjögren-Larsson syndrome
Neutral lipid storage disease
Netherton syndrome
Refsum disease
Trichothiodystrophy+Ichthyosis
Gene
ABCA12
TGM1, ABCA12
ALOXE3; ALOX12B
Ichthyin
Cytochrome P450
ALDH3A2
CGI-58 (ABHD5)
SPINK5
PAHX, PEX7
ERCC2; ERCC3
Lamellar Ichthyosis
Autosomal Recessive
 Incidence 1:200,000

 Primary
Features:
 Collodion
baby phenotype
 Plate-like, large, dark scale
 Ectropion, Eclabium
 Scarring alopecia
Lamellar Ichthyosis


Due to mutation in the TGM1 gene in
the vast majority of cases, coding for
Transglutaminase-1
A few common mutations exist (the
“German” splice-site mutation) and
R141 and R142 in exon 3.
 Few
families with mutation in ABCA12,
Ichthyin, and cytochrome P450 genes
Congenital Ichthyosiform
Erythroderma
Autosomal Recessive
 Incidence 1:200,000-300,000
 Primary features

 Collodion
baby presentation
 Bright red (erythrodermic) skin
 Fine, white scale
Congenital Ichthyosiform
Erythroderma

Due to mutation in many different genes, 5 of
which are known





ALOX12B and ALOXE3 (in about ~10%)
Ichthyin (in about ~10%)
A new cytochrome P450 gene
Enzymes encoded by these genes are
involved in lipid metabolism
Operate in common membrane arachidonic
acid pathway (lipoxygenase)
Harlequin Ichthyosis


Autosomal recessive
Mutation in ABCA12 gene


(ATP-binding cassette transporter protein)
Primary features:
Thick, armor-like plates of scale that fissure and
crack
 Eclabium and Ectropion
 Poor prognosis, although survivors have a
congenital ichthyosiform erythroderma phenotype

So what is a mutation,
anyway?
How do we detect a mutation?
• Chromosomes



• DNA



• Metabolic


Karyotype
arrayCGH
FISH
Sequence analysis
Mutation scanning
Targeted mutation
analysis
Analytes
Enzyme assay
What do we need for mutation
testing?

Material required
for testing:

Buccal swabs

Blood

Skin punch biopsy
How is DNA Sequencing Done?
Gly278Arg
What is the use of this
mutation information ?

Identification of disease-causing
mutation(s) allows answers to the
questions:
What do I have?
 Why do I have it or how did it happen?
 What is the chance it will happen again?
 What’s wrong with my skin and how best
can it be treated?
