Disorders of Keratinization

Dr. V. Swathi P
Definition
• The word ‘ichthyosis’ is derived from the Greek word
‘ichthys’, which means fish.
• Recently icthyosis has been classified as syndromic
and non‐syndromic in contrast, the onset of the
disease, namely the distinction between ‘congenital
onset’ and ‘non‐congenital onset’.
 Non Syndromic Icthyosis
Common ichthyoses
• Ichthyosis vulgaris (IV)
• Non‐syndromic recessive X‐linked ichthyosis (RXLI)
Autosomal recessive congenital ichthyosis (ARCI)
• Harlequin ichthyosis (HI)
• Lamellar ichthyosis (LI)
• Congenital ichthyosiform erythroderma (CIE)
• Self‐healing collodion baby
• Acral self‐healing collodion baby
• Bathing suit ichthyosis (BSI)
Keratinopathic ichthyosis (KPI)
• Epidermolytic ichthyosis (EI)
• Superficial epidermolytic ichthyosis (SEI)
• Congenital reticular ichthyosiform erythroderma (CRIE)
• Annular epidermolytic ichthyosis (AEI)
• Ichthyosis Curth–Macklin (ICM)
• Epidermolytic naevi
Other non‐syndromic forms
• Loricrin keratoderma (LK)
• Erythrokeratodermia variabilis (EKV)
• Inflammatory peeling skin disease (PSS type B)
• Exfoliative ichthyosis AR Keratosis linearis–
ichthyosis congenita–keratoderma (KLICK)
Common ichtyosis
 Icthyosis Vulgaris X-linked Icthyosis

Filaggrin gene STS gene encoding

Mutation: steroid sulphatase

Histidine, a basic Cholesterol

molecule for synthesis sulphate
of profilaggrin. accumulation in
epidermis.
 Icthyosis Vulgaris X-linked
Icthyosis

Impaired
squamous cell
formation, TEWL,
Epidermal
and develop
defect:
inflammatory
responses on
exposure to
allergens and
haptens
 Icthyosis Vulgaris X-linked
Icthyosis

After the first 3 months of After birth,

Onset: birth. present with a
very fine scaling
or peeling of the
skin

Skin is dry, with fine At 2–6 months,

scales that appear “pasted large thick dark
on” over the entire brown to yellow‐
body and are larger. brown
hyperkeratoses
 Icthyosis Vulgaris X-linked Icthyosis

Males = females Males > females

site Extensor surfaces of the limbs Hyperkeratoses

are severely involved. develop covering the
trunk, extremities
and neck

Flexural areas are spared. Dark hyperkeratosis

Scales prominent on the back giving the lateral
than on the abdomen aspects of the trunk
and the back of the
neck a ‘dirty look’
 Icthyosis Vulgaris X-linked Icthyosis

Palms / Diffuse hyperkeratosis Palms and soles are

Soles with linear grooves spared.
cross perpendicularly to
the thenar and
hypothenar eminences.

Assosiated 35%–50% of patients Kallmann syndrome,

features with IV have X‐linked
manifestations of atopy chondrodysplasia
punctata or with
mental retardation,
unilateral
polymicrogyria and
retinitis pigmentosa
Ichthyosis vulgaris. Recessive X‐linked ichthyosis.
 Histology
Icthyosis Vulgaris X-linked Icthyosis

Hyperkeratosis, nearly Orthohyperkeratosis and

absent granular layer often hypergranulosis

follicular keratotic plugging Marked follicular plugging

and in around 30% of patients

No keratohyalin granules by Ultrastructurally, increase

electron microscopy. of corneodesmosomes.
Treatment
• Soap is best avoided.
• After a bath or hydration of the skin, application of
emollients such as vegetable oils, liquid paraffin, or
Vaseline will prevent scaling and dryness.
• Warm moist climate can make therapy more effective.
• Urea (10%–15%) in a cream or ointment base is
effective.
• Other topical agents used include propylene glycol
(40%–60% v/v), salicylic acid (2%–3% in an ointment
base), and ammonium lactate lotion.
• A salt water bath help by hydrating the horny layer.
• Cetomacrogol additives enhance the antipruritic
effect of bath oils.
• Topical retinoids decrease scaling, but irritation of the
skin limits their use.
• Moisturizing cleansers and humidifiers are helpful.
• Systemic treatment with acitretin or isotretinoin is
possible but rarely necessary
Collodion Baby (Synonyms: Collodion Fetus, Ichthyosis
Congenita)
• Shared presentation of several congenital ichthyoses,
mostly with autosomal recessive inheritance
• Previously termed nonbullous ichthyosiform
erythroderma (NBIE), currently named as congenital
ichthyosiform erythroderma (CIE),is the commonest
condition (60%–80%) resulting from collodion baby,
followed by autosomal recessive LI.
• Incidence of premature birth is more.
• At birth, a parchment-thin, yellowish, plastic-like
membrane covers the whole body, tethering at body
orifices.
• There is a typical appearance, with ectropion,
eclabium, flat pinna, effacement of normal skin
creases, and sausage-shaped digits.
• Restricted limb movements
Collodion baby: Tough, inelastic, shiny,
collodion-like covering with ectropion

Shedding of dried up membrane

• Sucking and pulmonary ventilation is impaired, resulting
in dehydration, malnutrition, hypoxia, and pneumonia.
• Within first few days of life, membrane dries up with
fissuring around the flexures.
• Shed completely in the next few weeks and gradually
clinical features of specific forms of ichthyosis become
evident.
Diseases associated with collodion membrane
• Sjogren–Larsson syndrome,
• Self Healing Colloidon Baby,
• Trichothiodystrophy (TTD),
• AEC syndrome,
• Neutral lipid storage disease,
• Chondrodysplasia punctata,
• Loricrin keratoderma (LK),
• Gaucher disease,
• X-linked hypohidrotic ectodermal dysplasia
Autosomal recessive Congenital
Icthyosis
Harlequin ichthyosis
• Most devastating type of ARCI.
• Lethal in 44% of cases

Pathophysiology
• ABCA12 transfer lipids such as glucosylceramides, into
lamellar bodies.
• It also transport proteases such as kallikrein 5, 7, and 14
into lamellar bodies and secrete these proteins into the
intercellular space in the stratum corneum.
HPE: Hyperkeratosis, parakeratosis and hypergranulosis
Clinical Features:
• Very thick, yellow–brown plates

of scale that tightly encase the

neonate; large, deep, bright- red
and oozing cracks and fissures;
extreme ectropion, eclabium and
ear deformities
• 10% of children develop autoamputation of digits
• Respiratory problems are the major cause of death in
neonates
Lamellar ichthyosis (AR) and Congenital Icthyosiform
Erythroderma
• Characterized by large plate‐like dark‐brown
hyperkeratoses covering the entire body.
• At the other end marked erythroderma, with fine often
whitish or grey scales, pronounced palmoplantar keratosis
and have been referred to as having CIE
Pathophysiology
• Transglutaminase‐1 contributes to the assembly of the
cornified envelope by catalysing calcium‐dependent
crosslinking of proteins, such as involucrin, loricrin and
proline rich proteins and by binding Ω‐hydroxy ceramides
to involucrin, thus connecting the lipid envelope with the
CE.
• The epidermal lipoxygenases E3 and 12B act on
adjacent steps in the hepoxilin pathway and are
believed to play a role in the secretion of lamellar
bodies
• The NIPAL4 gene encodes for ichthyin essential for
skin barrier homeostasis.
• CYP4F2 encodes a cytochrome P450 polypeptide
homologue of a leukotriene B4 Ω‐hydroxylase.
• It participates in the hepoxilin pathway
• Mutations in CERS3 gene encoding ceramide synthase 3
- rare cause of ARCI
• Loss of function mutations leads to loss of very long acyl
chains from C26 up to C34 in terminally differentiating
keratinocytes and impair epidermal barrier formation.
• LIPN encodes acid lipase involved in triglyceride
metabolism ,expressed only in the epidermis.
• 2‐bp deletion in LIPN – presents with mild form of CIE
diffuse ichthyosis on the legs
• PNPLA1 belongs to the patatin‐like phospholipase
family
• PNPLA1 mutations feature fine white scales and
moderate erythroderma and PPK and a pseudosyndactyly
of the second and third toes
Clinical features
• The majority of patients having TGM1 mutations present
with classical LI often having complaints such as
ectropion or alopecia ichthyotica.
• There is no obvious erythroderma, but beneath the thick
scales some erythema can be present.
• Ears are often deformed and small.
LI: Brownish, large, quadrilateral,
adherent scales

Palmar keratoderma
Congenital ichthyosiform erythroderma: Ectropion
Diffuse erythema and scaling
• Moreover, there is a group of patients who initially
present as collodion babies, progress to mild CIE and
later may present with a very mild or even absent
scaling.
• This phenotype is referred to as Self‐improving
congenital ichthyosis.
Self‐improving congenital ichthyosis.
• Neonates with lipoxygenase mutations are born with
a mild collodion and later present with the CIE
phenotype, although some also present brownish
scales.
• Typically, they show a striking palmoplantar
hyperlinearity which is reminiscent of the accentuated
creases in IV
Clinical phenotype of ALOXE3 mutations. Note palmoplantar
hyperlinearity resembling accentuated creases in ichthyosis
vulgaris
• However, mild keratotic lichenifications of the elbow
fossa or of the dorsum of the hands help to rule out this
differential diagnosis.
• Patients may progress to SICI
• Those with ALOX12B mutations more often exhibit
pronounced palmoplantar keratosis than patients with
ALOXE3 mutations
• Patients with NIPAL4 mutation often present with a
CIE/LI overlapping phenotype, ectropion, clubbing of
the nails and a pronounced and diffuse yellowish
keratoderma on the palms and soles
Clinical phenotype of NIPAL4
mutations. Diffuse yellowish
keratoderma on palms and soles.
Reticulate scaling on the trunk
• Patients with CYP4F2 mutations present with a CIE or
mild collodion baby phenotype at birth
• As the children grow older, they develop whitish‐grey
scales which are more pronounced in the periumbilical
region
• Palms and soles show pronounced hyperlinearity or even
PPK.
• Mutations in CERS3 - born as collodion babies,
progress to CIE, improvement of the ichthyosis in
summer.
• Marked plantar hyperlinearity, pruritus, recurrent
uncomplicated bacterial and Pityrosporum
infections.
Clinical phenotype of CERS3 deficiency. Mild plantar keratoderma
with hyperlinearity.
• LIPN mutations seem to cause a late‐onset form of
ichthyosis at the age of 5 years, so that it is not
formally a congenital ichthyosis, although it belongs
pathophysiologically to the ARCI spectrum
Investigation:
• Clinical;
• Electron microscopy; in situ transglutaminase-1
expression and activity assay;
• Molecular testing.
Bathing suit icthyosis
• Recombinant expression of the TGM1 mutations in BSI
showed that they exhibit a marked shift in temperature
optimum from 37°C to 31°C.
• Deficient activity of BSI mutants could be rescued and
even reconstituted by decreasing the temperature to below
33°C.
• All BSI mutations showed an activity above 10% at their
temperature optimum at 31°C and a dramatic decrease at
37°C
Clinical features
• Born as collodion babies
• Shedding of the collodion membrane is followed by the
development of large dark grey/brownish scales affecting
the trunk and the scalp, but sparing the face and
extremities.
• Palms and soles are dry and diffusely mildly
hyperkeratotic.
• Worse in the summer and improve in winter.
• Hypohydrosis as is often seen in ARCI may play a
crucial role in local heat accumulation that results in
additional reduction of TG1 activity
• Hyperkeratoses can develop in the ear canal affecting
the ability to hear.
Digital thermography validated a striking
correlation between warmer body areas and the
presence of scaling in patients
Management of congenital ichthyoses
• These neonates are taken care of in a neonatal intensive
care unit
• Collodion babies should be placed in a high humidity
incubator with close monitoring of body temperature.
• Recommended to start with humidity in range of 60–80%,
and to decrease every 3–4 days in order to reach normal
humidity conditions, so that the children can be
transferred to an open crib.
• Bland ointments, e.g. a dexpanthenol containing
ointment two to four times a day.
• Percutaneous absorption is very high and substances
typically used in older children with ichthyosis, such as
urea or lactic acid should be avoided in the first year of
life.
• Salicylic acid is contraindicated as it may result in
metabolic acidosis and death within 72 h even when
used in low concentrations such as 3%.
Issue of bathing
• There is beneficial effect of bathing for ARCI and KPI
and in particular with bath additives such as sodium
bicarbonate
• It has been shown that two handfuls of baking soda to a
bath tub will raise the pH from 5.5 to 7.9
• Ocean water that many patients also report to be
beneficial usually has a pH above 8.1
• It is conceivable that mild alkalinization of the skin
raises the pH to an optimum for serine protease
activity such as KLK5 and KLK7
• Other popular bath additives are wheat corn or rice
starch or bran, e.g. in Netherton syndrome.
• Antiseptics as bath additives can become necessary,
e.g. in KPI, to overcome bad odour.
• Oils are usually messy and not recommended.
Practical treatment options for daily care
• Patients with ARCI or KPI generally need to bath at
least once a day.
• After soaking the skin for around 20–30 min, the patient
or a parent can use a sponge, microfibre cloth or silk
glove to rub the skin and thus provide mechanical scale
removal as well as cleansing (i.e. removal of remaining
ointment).
• This again may take another 20–30 min.
• Drying with a towel and the immediate application of
ointments should be done while the skin is still wet.
• A variety of topical ointments can be used but local
availability as well as composition will depend on the
country and its traditions.
• Urea‐based ointments (up to 10%) and lactic acid
based ointments (up to 12%) as well as glycerol
based ointments are widely used.
• Substances such as macrogol 400 or propylene
glycol can decrease the scaling and work as
keratolytics.
• Tazarotene gel has been recommended for the treatment
and prevention of ectropion.
• N‐acetylcysteine blocks cell‐cycle progression in the G1
phase and has an antiproliferative effect.
Systemic treatment options
• LI – require rigorous treatment and usually benefit from
systemic retinoids as well as from urea or lactic acid
containing ointments.
• CIE may respond less well to systemic retinoids – some
even can get worse – and also they tolerate moisturizers
such as lactic acid or urea less well.
• EKV is known to respond rapidly to low‐dose treatment
with retinoids
• In patients with HI, the use of retinoids is warranted,
even in newborns
• Patients suffering from EI due to KRT1 mutations have a
strong risk of exacerbation of the disease when given
retinoids, while those with KRT10 mutations may benefit
when given a low dosage, e.g. up to 0.5 mg/kg body
weight.
• Superficial EI responds well to low retinoid doses
• Patients with ichthyosis may be treated when they are
over the age of 16 or who have stopped growing
significantly.
• In women of child‐bearing age, isotretinoin prefered over
acetretin
• ‘Drug holidays’ are popular in particular when using
isotretinoin.
• A side effect of alitretinoin therapy may be
hypothyroidism that can cause tiredness and it seems
to be advisable to monitor thyroid stimulating
hormone (TSH) levels in these patients
Special aspects of treatment
Eye.
• Surgical corrective treatment of chronic ectropion

• Basal cell carcinoma may be masquerading as chronic

ectropion in LI.
Ear.
• Ear canal has to be professionally cleared of horny
material (every 4 weeks)
Hair.
• Treatment of the scalp poses special problems and
requires washable preparations.
Hypohydrosis.
• Oral retinoid treatment can normalize sweat gland
function and markedly improve the quality of life in
ARCI patients
Musculoskeletal system.
• Physiotherapy is of enormous value, e.g. to treat
flexural contractions.
Vitamin D.
• Lamellar types of ichthyoses as well as CIE including
Netherton syndrome are important risk factors for 25‐
hydroxyvitamin D deficiency with secondary
hyperparathyroidism
Superinfections.
• Some forms of ARCI or KID syndrome may be
associated with a higher incidence of dermatophytosis
(Trichophyton rubrum infection may even mimic EI)
Keratinopathic icthyosis:
Keratinopathic icthyosis:
• Mutations in keratin genes like KRT1, KRT10, or KRT2.
• Keratin aggregates interact with activated MAP kinases,
molecular chaperones such as Hsp70 and components of
the ubiquitin‐ proteasome system and contribute to
inflammatory changes.
• These keratin aggregates can be induced by trauma or
environmental conditions, e.g. high temperature, fever or
skin infections, that are known modulators of disease
severity.
Epidermolytic ichthyosis
• Born with Congenital Icthyosiform Erythroderma.
• ‘burned child/enfant brule’

• In the first month, blistering resolves and hyperkeratosis

develops instead.
• However, fragility of skin remains
• The older child and adults present with rippled
keratotic ridges,in axilla,elbows and flexural aspects of
the knees.
• On knees and the lower legs,present with spiny
hyperkeratosis
• In KRT10 mutations, palms and soles are usually
spared, with KRT1 mutations have severe involvement
of the palms and soles.
• Use of systemic retinoids worsen their skin condition.
Epidermolytic hyperkeratosis
Investigations
• Striking histology, namely Epidermolytic hyper
keratosis
• In superficial EI, this finding is less marked and
expressed mainly in the stratum granulosum and upper
epidermis, and it may be important to take a biopsy
from a site of maximal clinical involvement, e.g. from
the knees.
• Similar considerations apply for annular EI.
• Ultrastructure of these diseases is characterized by
collapsed keratin aggregates (tonofilaments).
• These aggregates often form around the cell nucleus,
have lost their connection to the desmosomes and
therefore promote intraepidermal blistering.
Superficial epidermolytic ichthyosis (Ichthyosis
bullosa Siemens )
• Presentation of resembles that of EI.
• Milder and more localized, large parts of the body are
clear.
• Keratosis is limited to the region around the navel and on
the dorsal aspects of the hands and feet or the arm and the
axillary region
(a) Dark grey hyperkeratosis over trunk. (b) Dark grey hyperkeratosis over extremities and
cheeks
• A phenomenon that is quite typical is superficially
denuded areas.
• For this phenomenon Siemens who first described the
disease in 1937 coined the German term ‘Mauserung’
(moulting)
peeling of the hyperkeratotic skin with underlying normal skin without any
erythema (“Mauserung” phenomenon). Note the collarette of scales in the
margins
Annular epidermolytic ichthyosis
• Mild variant of EI which shares a similar onset at birth,
bouts of disease activity with development of
numerous annular and polycyclic hyperkeratotic
lesions especially on the trunk and extremities
• Outbreak of disease flares can be associated with high
temperature in the summer, fever or pregnancy
Erythematous polycyclic plaques over the trunk with exfoliation starting from the
center. (b) Exfoliation extending toward the periphery giving an annular appearance
Congenital reticular ichthyosiform
erythroderma
Ichthyosis variegata
Ichthyosis en confettis
• Pathophysiology
• KRT10 mutations.
• Initially display generalized erythema and scaling with
subsequent localized spontaneous healing which
manifest with small pale white spots.
• The revertant phenotype is due to multiple
recombination events in the KRT10 gene, which can be
considered as a kind of natural gene therapy.
• Clinical features
• ‘Confetti ichthyosis’.
• Characterized by very severe CIE and from the age of
3 years by the gradual onset of hundreds of pale
normal‐ appearing confetti‐like spots which can grow
up to 2 cm in size
• Many of these patients are severely ill and fail to
thrive.
• Often there is osteomalacia, for instance affecting the
ankle joints.
confetti‐like spots representing localized
spontaneous healing
Ichthyosis hystrix Curth–Macklin
• Variable phenotype: mild to severe, mutilating
palmoplantar keratoderma; hyperkeratosis with
verrucous, cobblestone or hystrix-like pattern on
extremities and trunk
Pathophysiology
• Pathogenic mutations in KRT1 affect the variable tail
domain (V2) of keratin 1 and result in a profoundly
different abnormality of the cytoskeletal architecture
than in EI.
Clinical features
• The skin of patients with ICM is characterized by
extensive spiny hyperkeratosis (‘hystrix’‐like)
covering the entire body and involving the palms and
soles
Other non syndromic icthyosis
Erythrokeratoderma
• Localized conditions were characterized by erythema
and hyperkeratosis
• Clinical expression of molecular defects can be quite
variable,.
Erythrokeratoderma variabilis (Mendes da Costa
syndrome)
• Characterized by migrating polycyclic erythematous
lesions accompanied by hyperkeratosis.
• In many dominant negative mutations in GJB3 encoding
connexin 31 or GJB4 encoding connexin 30.3 have been
found
• Connexins form gap junctions, which are aqueous
intercellular channels that are found in all tissues
including skin, nervous tissue, heart and muscle
Clinical features
• Onset in infancy.
• There are two types of lesions: relatively fixed well‐
demarcated keratotic and erythematous plaques, often
bizarrely shaped, which show a predilection for
extensor surfaces, lateral trunk and buttocks and extend
and regress in area thickness and degree of erythema;
• Transient erythematous, polycyclic or comma‐shaped
macular lesions occurring at any site.
Management
• Acitretin treatment is the treatment of choice
• Beneficial effect of low‐dose isotretinoin has been
reported
Progressive symmetrical erythrokeratoderma
• Gottron syndrome
• Clinical variant of erythrokeratoderma with striking
symmetrical appearance.
Pathophysiology
• Same connexin genes mution that underlie
erythrokeratoderma variabilis.
• G12D in the gene GJB4 has been identified
Clinical features
• Normal at birth.
• Large geographical but symmetrical fine scaly plaques
with an orange‐red erythema appear in infancy
• There is little pruritus and the lesions are non‐
migratory in nature, as opposed to classical EKV.
• The shoulder girdle, cheeks and buttocks are most
often affected.
Symmetrical acrokeratoderma
• Brown to black hyperkeratotic plaques were
symmetrically distributed over the acral regions with
marked worsening of the condition in the summer and
improvement during winter.
• Clinically,whitish hyperkeratosis on the back of both
hands and fingers and the wrists in particular after 5
minute water immersion reminiscent of aquagenic
keratoderma.
Keratosis linearis–ichthyosis congenita–sclerosing
keratoderma (KLICK)
• Like LK, it is dominated by keratoderma
• Abnormal function of the POMP gene product may lead to
increased stress of the endoplasmic reticulum (ER).
• The so‐called ER stress interferes with epidermal
differentiation as has been shown in connexin disorders.
Clinical features
• A more sclerosing variant of loricrin PPK associated
with mild congenital ichthyosis.
• In contrast with LK, it is inherited in an autosomal
recessive fashion.
• Affected individuals demonstrate keratotic punctuate
plugs or papules that are distributed in a linear pattern
and are found on the flexural areas of the extremities – a
distinct and probably pathognomonic phenotype
Keratotic punctuate plugs or papules that are distributed
in a linear pattern and are found on the flexural areas of
the extremitie
Investigations
• Ultrastructure confirms the histological finding of
hypergranulosis and shows abnormally large
keratohyaline granules.
Exfoliative ichthyosis
• Loss‐of‐function mutations in the CSTA gene
encoding the protease inhibitor cystatin A are the
cause of this autosomal recessive disease
• Functional and ultrastructural data show that the
defect manifests mainly within the basal and
suprabasal layers of the epidermis characterized by
expression of keratin 14.
Exfoliative ichthyosis with
pronounced plantar keratoderma.
• Clinical features
• Pronounced PPK, which tends to be sensitive to
sweat and water exposure, similar to acral peeling
skin syndrome (PSS), the Bothnia type of non‐
epidermolytic PPK (NEPPK), or aquagenic PPK.
• Mild dry and scaly skin.
• Skin peeling may occur, easily elicited by moisture or
minor trauma, and resemble the ‘moulting’
phenomenon in superficial EI
• Management
• Efficient symptomatic treatment options seem
completely lacking, because local therapy tends to
increase humidity‐associated sensibility.
Loricrin keratoderma
• Variant Vohwinkel syndrome
• Mutilating keratoderma with ichthyosis

• Camisa syndrome

Pathophysiology
• Mutations in the LOR gene encoding loricrin, a glycine‐
rich cornified envelope protein.
• The mutant protein interfere with the regulation of
cornification.
Clinical features.
• Collodion babies
• Ichthyosis is generally mild and may pass unnoticed.

• Rugose keratoderma develops during childhood,

gradually extending to the confluent honeycomb pattern
Loricrin keratoderma
• The edges of the keratoderma are diffuse (in contrast
to true Vohwinkel syndrome) and cicatricial bands
(pseudo‐ainhum) may develop around the digits.
• Knuckle pads and warty keratoses have been reported,
but are not a prominent feature.
• Hence, the combination of honeycomb keratoderma
with mild non‐syndromic ichthyosis is typical,
Investigations
• Histologically - hyperkeratosis, hypergranulosis and
parakeratosis
• Electron microscopy - dense intranuclear granules in granular
cells, thin cornified cell envelope in the lower cornified layers
• Immunoelectron microscopy - the presence of loricrin in
these nuclei.
Management
• The successful use of isotretinoin has been reported
• Inhibitors of VEGF receptor 2.
Thank you