1 University of Medicine and Pharmacy “Carol Davila”

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University of Medicine and Pharmacy
“Carol Davila”, Bucharest
Faculty of Medicine

Thesis Work

Rare Dermatological Diseases – Experiences of
Tertiary Care Referral Hospital

Scientific Coordinator Graduate
Prof. Univ. Dr. Carmen Salavastru Toluwalope Mary Areje
Bucharest
2018

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Contents
General Part 6
Introduction 6
1.Epidemolysis Bullosa 8
1.1 Epidemiology 8
1.1.1 Epidemiology in Romania 9
1.2 Pathology 10
1.2.1 EB simplex 11
1.2.2 Junctional EB 12
1.2.3 Dystrophic EB 13
1.2.4 Kindler’s Syndrome 14
1.3 Clinical Manifestations 14
1.3.1 EB Simplex 16
1.3.2 Junctional EB 17
1.3.3 Dystrophic EB 19
1.3.4 Kindler’s Syndrome 22
1.4 Diagnosis 22
1.4.1 Skin Biopsy 23
1.4.2 Immunoflorenece microscopy 23
1.4.3 Genetic Testing 24
1.4.4 Prenatal Testing 24
1.4.5 Blood tests 24
1.4.6 Imaging Tests 25

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1.5 Management/Treatment 25
1.5.1 Medical treatment 25
1.5.2 Surgical Treatment 27
1.5.3 Clinical Trials 29
2 Ichthyosis 30
2.1 Epidemiology 30
2.2 Pathology 31
2.2.1 Ichthyosis Vulgaris 32
2.2.2 X-linked recessive Ichthyosis 32
2.2.3 Harlequin Ichthyosis 33
2.2.4 Epidermolytic hyperkeratosis 33
2.2.5 Lamellaer Icthyosis 34
2.2.6 Acquired Ichthyosis 34
2.2.7 Sjogren-Larsson Syndrome 35
2.3 Clinical Aspects 35
2.3.1 Cutaneous 35
2.3.2 Ocular and Periocular manifestations 36
2.3.3 Complications 38
2.4 Diagnosis 38
2.4.1 Laboratory Studies 38
2.4.2 Imaging Studies 39
2.5 Management/Treatment 39
2.5.1 Medical Care 40
3 Nethertons Syndrome 42
3.1 Epidemiology 42

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3.2 Pathology 42
3.3 Clinical Aspects 42
3.4 Diagnosis 43
3.4.1 Blood test 43
3.4.2 Light microscopy 43
3.4.3. Electron microscopy 43
3.5 Management/Treatment 44
4 Neurofibromatosis 45
4.1 Epidemiology 45
4.2 Pathology 45
4.2.1 NF1 45
4.2.2 NF2 46
4.3 Clinical Aspects 46
4.3.1 NF1 46
4.3.2 NF2 49
4.4 Diagnosis 50
4.4.1 NF1 50
4.4.2 NF2 50
4.5 Management/Treatment 51
4.5.1 NF1 51
4.5.2 NF2 51
5 Tuberous Sclerosis 53
5.1 Epidemiology 53
5.2 Pathology 53
5.3 Clinical Aspects 53

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5.3.1 Cutaneous Lesions 53
5.3.2 Non- cutaneous Lesions 54
5.4 Diagnosis 56
5.4.1 Clinical diagnosis Criteria 56
5.4.2 Genetic Diagnosis 57
5.5 Manangement/Treatment 57
5.5.1 Medical care 58
5.5.2 Surgical care 58

Practical Part 59
6 Objectives 59
7 Materials and Methods 59
7.1 Materials
7.2 Methods
8 Results 62
8.1 Epidemolysis Bullosa 63
8.2 Ichthyosis 68
8.3 Neurofibromatosis 73
8.4 Tuberous Sclerosis 76
9 Discussion 79
10 Conclusion 80
11 References 81

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General Part
Introduction
Tertiary care is highly specialized medical care over a certain period of time that involves advanced
and complex procedures and treatments performed by medical specialists in specialist clinics or
facilities.
There are thousands of dermatological diseases that can be found in tertiary care clinics.
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of
the population. Most rare diseases are genetic, and are present throughout a person’s entire life, even
if the symptoms do not appear immediately. In Europe, a disease or disorder is defined as rare when
it affects less than 1 in 2000 citizens. Rare diseases are characterised by a wide diversity of symptoms
and signs that vary not only from disease to disease but also from patient to patient suffering from the
same disease. 1
In this thesis I will discuss five rare dermatological conditions. These are:
? Epidermolysis Bullosa,
? Ichthyosis,
? Netherton’s Syndrome, which is a subtype of Ichthyosis,
? Neurofibromatosis
? Tuberous Sclerosis Complex.
Epidermolysis Bullosa is a rare dermatological disorder where the skin is extremely fragile, as a
result, recurrent blister formation occurs in response to minor trauma.
Ichthyosis is a congenital dermatological disease in which the skin is dry and scaly and appear to look
like fish scales.
Netherton’s Syndrome, which is a subtype of Ichthyosis is an autosomal recessive disorder caused by
mutations in the SPINK5 gene.
Neurofibromatosis is an autosomal dominant disorder characterized by the development of multiple
benign tumours of nerves and skin called neurofibromas.

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Tuberous Sclerosis is an autosomal dominant disorder that results from mutations in
the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems
including the brain, eyes, heart, kidney, lungs and the skin.
These dermatological conditions mentioned above are mainly caused by genetic mutations and family
genetics. There is no cure for any of these dermatological diseases, however the goal is to give the
patient the best quality of life possible. The methods of treatment are constantly being developed and
improved.
I chose this topic because I am interested in pursuing a career in dermatology after medical school.
Completing my thesis in dermatology will help me to learn more about dermatology as a speciality.
I also wanted to learn more about diseases in dermatology that are not common. This topic has
allowed me to learn about rare diseases in dermatology.

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1.Epidermolysis bullosa (EB)
Epidermolysis bullosa is a group of inherited bullous disorders characterized by extremely fragile
skin and recurrent blister formation in response to mechanical trauma.2, 3
Epidermolysis bullosa (EB) is a genodermatosis that affects mainly the skin and mucosal membranes.
The onset of EB usually occurs immediately after birth. In the most severe forms, the disease becomes
systemic meaning it can affect the teeth, joints, the patient’s protein, vitamin and mineral deposits,
causing severe malnutrition. The manifestations are various, ranging from mild symptoms that
include minor skin problems, up to life threatening ones, which include severe damage to the skin,
mucosa, limb mutilations such as pseudosyndactyly (mitten hands deformity), severe malnutrition
and skin cancer (Squamous cell carcinoma type). 4, 5, 6

1.1 Epidemiology
The prevalence of EB varies for different parts of the world. There seems to be much higher
occurrence of EB in Western European countries and the USA than countries in Eastern Europe such
as Romania and also countries like Japan. In Romania this might be because of the underreporting of
mild cases such as EB simplex.
The prevalence of epidermolysis bullosa is 11.07 cases per 1 million live births. The prevalence
epidermolysis bullosa cases in Norway is 54 cases per million live births, in Japan is 7.8 cases per
million live births. In Australia is 10.3 cases per million live births, and in Croatia is 9.6 cases per
million live births. 2
During the period 1992–1996, the prevalence of EB in Scotland was reported to be 49 cases per 1
million inhabitants.6

A study in Italy, between the years 1991 till 2009, 880 cases of EB have been reported in Italy,
indicating a prevalence of 15.4 cases per million. Of these, 258 patients presented EB simplex, 82
patients were diagnosed with JEB, 524 patients with DEB and in 16 cases, and the EB type could not
be identified.6

In the U.S, a study was performed over a period of 16 years from the year 1986 till 2002. The
estimated prevalence was 8 per 1 million, and the incidence was 19 per 1 million live births. 6

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Another large study was conducted in Australia and New Zealand, over a period of 2.5 years, between
2006 and 2008. There were 259 patients reported to have EB. 139 patients with EBS, 91 with
dystrophic EB, 28 with JEB and 1 with Kindler syndrome. The recorded prevalence of EB was 10.3
cases per 1 million inhabitants. 6

1.1.1 Epidemiology in Romania (2006-2012)
In Romania, there was a total of 89 cases of EB were reported between the years 2006 and 2012.
Fifty-eight of these people had dystrophic EB (DEB). There were twenty who had simplex EB
simplex (EBS), one patient who had kindler syndrome and ten patients whose type of EB couldn’t be
determined. The female: male sex distribution is 1.3:1, the majority of EB patients were females. 6
The graph below shows the age categories of the patients who were diagnosed with EB in Romania.
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The prevalence of EB in Romania is 89/20 121 641. This is 4.42 cases per 1 million people. EB
incidence in Romania is 25 cases per 1 million newborns. 6
Romania seems to have a much lower rate of EB than other countries in Europe. This could be because
of many factors. EB patients might not seek medical help from a dermatologist who can diagnose the
disease. Secondly, the low socio-economic status and inappropriate medical care in certain
environments within Romania dramatically increase the mortality rate and thirdly, the lack of
awareness of general practitioners regarding rare disorders could mean that less patients are
diagnosed.6

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1.2 Pathology
This condition caused by an imbalance of basement membrane components due to underlying genetic
mutations. These mutations affect several structural proteins within the keratinocyte or the skin
basement membrane zone. The basement membrane is the part of the skin that connects the dermis
to the epidermis. EB can be transmitted as either an autosomal dominant or autosomal recessive
disease, this depends on the subtype. 2, 4
The image below (Figure 1) shows the basement membrane and the protein structures with the BMZ.
It also shows where each type of EB occurs in the layers of the skin.

Figure 1 Adapted from BOEIRA, ET ALL. (2013). Inherited epidermolysis bullosa: clinical and therapeutic
aspects. Anais Brasileiros de Dermatologia, 88(2), 185-198.
Epidermolysis bullosa is classified into four major categories based on the location of the cutaneous
lesion:
? Epidermolysis bullosa simplex (EBS) – intra-epidermal skin separation.
? Junctional epidermolysis bullosa (JEB) – skin separation in lamina lucida.
? Dystrophic epidermolysis bullosa (DEB) –sub-lamina densa
? Kindler syndrome – multiple levels of the skin.

EBS includes all subtypes of EB having mechanical fragility and blistering only in the epidermis.
EBS was further separated into suprabasal and basal subgroups, based on the histopathologic site of
cleavage within the epidermis.
JEB includes all subtypes of EB in which blisters develop within the lamina lucida of the skin
basement membrane zone (BMZ).

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DEB includes all EB subtypes in which blistering occurs within the uppermost part of the dermis.
Kindler syndrome is characterized by the presence of clinical phenotypic features unique among EB
such as photosensitivity and blistering that arises in multiple levels within and beneath the BMZ.4

Table I (below) – shows the types of EB based on the level of blister formation in the skin.
Level of blister formation in each major EB type.4

Major EB Types Level of Blister Formation
EB simplex Intra-epidermal
Junctional EB Intra-lamina lucida
Dystrophic EB Sub-lamina densa
Kindler syndrome Multiple levels (intra-lamina lucida and sub-lamina densa)
Table I
1.2.1 Epidermolysis bullosa simplex (EBS or EB simplex)
This is the most common type of EB. It develops in the outer layer of skin called the epidermis. It
mainly affects the palms and the feet. The blisters usually heal with minimal scarring. This type of
EB is a result of dominant negative mutations in either keratin 5 or keratin 14 gene. EBS with mottled
pigmentation is caused by mutations within the keratin 5 gene. EB simplex with muscular dystrophy
is caused by mutations within the gene for plectin, a protein which links the three components of the
cytoskeleton which are actin microfilaments, microtubules and intermediate filaments. An absence
of plectin leads to disorganisation of the muscular sarcomere. A rare autosomal recessive form of EB
simplex is caused by mutations in the keratin 14 gene.4, 5, 7
There are two main subtypes of EBS, these are suprabasal and basal EBS. This classification is based
on the histopathology and the level of blistering in the epidermis. Suprabasal EBS, the patient will
have blisters in the suprabasal part of the epidermis. In Basal EBS, the patient will have blisters at the
basal level of the epidermis. 9
The table below, (Table II) shows the clinical subtypes of EBS and the mutated proteins and genes
involved.

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Table II after FINE, JO-DAVID, ET AL. “Inherited epidermolysis bullosa: updated
recommendations on diagnosis and classification.” Journal of the American Academy of
Dermatology 70.6 (2014): 1103-1126.
EBS can be classified into three types:- generalised, localised and herpetiform. 5
1.2.2 Junctional epidermolysis bullosa (JEB)
This type of EB can be severe, with blisters beginning in infancy. It is inherited in an autosomal
recessive manner. This type of EB develops within the Lamina Lucida part of the skin. A baby with
this condition could develop a hoarse-sounding cry from continual blistering and scarring of the
vocal cords. JEB is caused by mutations of any of the three genes which encode for the three-
chained adhesion molecule, laminin-332. The presence of this mutation with this disease facilitates
rapid DNA screening in many patients. A minority of JEB patients have mutations within the gene
encoding for type XVII collagen.4, 5, 7
The table below, (table III) shows the subtypes of JEB and the mutated proteins and genes involved.

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Table III after FINE, JO-DAVID, ET AL. “Inherited epidermolysis bullosa: updated recommendations on diagnosis
and classification.” Journal of the American Academy of Dermatology 70.6 (2014): 1103-1126.
1.2.3 Dystrophic epidermolysis bullosa (DEB)
The lesions in DEB occur in the dermis. This type is related to a flaw in the gene that helps produce
type VII collagen (COL7A1) that provides strength to the dermis layer of the skin. If this substance
is missing or doesn’t function, the layers of the skin won’t join properly and the skin will be fragile.
This type of EB forms blisters that heal with scarring and milia formation. This is the most common
type of EB in Romania.4, 5, 7

The table below (table IV) shows the subtypes of DEB and the mutated genes involved.

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Table IV after FINE, JO-DAVID, ET AL. “Inherited epidermolysis bullosa: updated
recommendations on diagnosis and classification.” Journal of the American Academy of
Dermatology 70.6 (2014): 1103-1126.
1.2.4 Kindler’s Syndrome
Kindler syndrome is a type of EB caused by a loss of function mutation of the FERMT1 gene (also
known as kindlin-1). FERMT1 encodes a 677–amino acid protein which binds ?1, ?3 and ?6 integrin
cytoplasmic domains. The integrin family mediates cell adhesion to the basement membrane, and
absence of kindlin-1 results in poor anchoring of the basal layer of the epidermis to the underlying
basement membrane.
Kindlin-1 is a human homolog of the protein UNC-112. Protein UNC-112 is a membrane-associated
structural and signalling protein that had been involved in the linking of actin cytoskeleton to the
extracellular matrix. 4, 8
Kindler syndrome is the first genodermatosis caused by a defect in actin-ECM linkage.
Kindler syndrome keratinocytes show an up-regulation of basal level pro-inflammatory cytokines
interleukin –1?, IL-6, and tumour necrosis factor-? (TNF-?). 4, 8
Kindlin-1 expression has also been shown to prevent premature ageing in keratinocytes, as well as
regulate microtubule function in mitosis. Up-regulation of numerous other cytokines has been
described, resulting in the activation of fibroblasts to secrete ECM proteins and differentiate into
myofibroblasts. 4, 8
1.3 Clinical aspects
In EB, cutaneous manifestations include, mechanically fragile skin that easy forms blisters or erosions
especially on the hands and feet (acral distributions). Milia are formed, these are tiny firm white
papules, resembling cysts or pustules. Milia are more commonly found in dystrophic EB. The Nails
in patients with EB can be dystrophic or atrophic. Atrophic scarring on the skin occurs making it to
appear thin. The skin on the palms and soles of feet are thickened. Scarring alopecia occurs due to
blisters located on the scalp.
Exuberant granulation tissue can be found on patients who have EB. This is often seen in the
following locations on the body – Periorificial, axillary vaults, nape of the neck, lumbosacral spine;
periungual and proximal nail folds, confluent keratoderma of the palms and soles, post inflammatory
hypo- or hyperpigmentation; mottled or reticulate hyperpigmentation. 4, 8

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EB not only affects the hair, skin and nails but it also affects the mucosa. This can lead to blisters in
the mouth and throat, dental problems such as tooth decay, and dysphagia due to blisters and scarring
in the oesophagus. 7
The image below shows a typical non-inflammatory blister which is often seen in patients who have
EB. 4

Figure 2 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.

Figure 3 from- FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.
The image above shows atrophic scarring and post-inflammatory hypopigmentation on the
extremities found in dystrophic EB.

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1.3.1 EB simplex
Most epidermolysis bullosa simplex cases consist of keratin disorders characterized by intraepidermal
blistering with mild internal involvement. Cutaneous lesions caused by EB simplex typically heal
without scarring. 2
The image below (Figure 4) shows a blister or bulla on the foot of a child who has EB simplex.

Figure 4 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12
EBS Localised
This is a subtype of EB simplex. Is the localised form of EB simplex. This is the most common form
of epidermolysis bullosa simplex. Blisters are usually caused by a clearly identified traumatic event.
The blisters can range from mild to severe. These blisters occur most frequently on the palms and
soles. Hyperhidrosis (excessive sweating) can also be seen in patients with this subtype of EB
simplex. 2
Generalised EB simplex
EB simplex presents with a generalized onset of blisters with congenital origin. The extremities are
the most common sites of involvement. Palmoplantar hyperkeratosis and erosions are common.
Blisters heal with atrophy, and nails are often affected. Mucosal involvement can take place however,
is more common in the more severe subtypes. 2

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1.3.2 Junctional EB (JEB)
Junctional epidermolysis bullosa is a collection of diseases characterized by intra-lamina lucida
blistering.
Severe generalised form of JEB
The severe generalized form of junctional epidermolysis bullosa is characterized by generalized
blistering at birth and is caused by an absence or a severe defect in expression of the anchoring
filament glycoprotein laminin-332. 2
Patients with lethal forms of junctional epidermolysis bullosa show periorificial erosions around the
mouth, eyes, and nostrils, often accompanied by significant hypertrophic granulation tissue. 2
Multi-systemic involvement of the corneal, conjunctival, tracheobronchial, oral, pharyngeal,
oesophageal, rectal, and genitourinary mucosae is present. Internal complications of the disease
include a hoarse cry, cough, and other respiratory difficulties. Patients with severe generalized
junctional epidermolysis bullosa are at increased risk for death from sepsis or other complications.
These patients usually do not survive past infancy. 2

Figure 5 – shows an infant with JEB from the archive of Colentina Clinical Hospital –Children Dermatology Department.

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The image above shows an infant with severe generalised JEB on the lower limbs. There are erosions
on the feet and on the anterior part of the legs.

Generalised Intermediate JEB
This type of JEB is non-lethal but is generalized. Some patients can have significant mucosal
involvement. Those with a more significant phenotype with mucosal involvement usually have partial
loss of laminin-332. These patients have periorificial erosive hyper granulation tissue as those with
the severe variant. They can also show oropharyngeal, oesophageal, and urogenital erosions and
scarring. Enamel hypoplasia can lead to tooth abnormalities, and nail dystrophy or loss of nails can
occur. This group of patients with significant mucosal involvement survives infancy but their life
expectancy is reduced. 2, 5

Another subtype in the generalized intermediate junctional category are patients with loss of the
basement membrane protein BP180/collagen XVII. Patients with this subtype often have generalized
cutaneous blistering present at birth. Blistering activity is worsened by increased temperature. The
blisters formed heal with a distinctive atrophic appearance. Extracutaneous involvement is rare,
however the teeth can be affected with hypoplastic enamel formation which can lead to significant
tooth decay. Nail dystrophies and a non-scarring alopecia are common clinical signs. Individuals with
generalized atrophic benign epidermolysis bullosa have the potential to bear children and have a
normal life expectancy. 2, 5

Figure 6 from MARINKOVIC P.M, BAUER A.E. “Inherited Epidermolysis Bullosa” Wolff Klaus et al, Fitzpatrick’s
dermatology in general medicine, 7th ed, New York, McGrawhill Medical, 2008:505-516

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The image above (figure 6) shows periorificial erosions and hypertrophic granulation tissue in a
patient with JEB. 5

Localised JEB

Patients with localized junctional epidermolysis bullosa can present with blistering predominantly
localized on the pretibial region, upper and lower limb extremities. This is a less common than the
generalized subtypes. 2, 5

Figure 7 below shows a child with exuberant granulation tissue on the nape of the neck. This particular
lesion occurs in JEB.

Figure 7 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.
1.3.3 Dystrophic EB (DEB)
This is a group of diseases caused by defects of the anchoring fibrils in the sublamina-densa part of
the skin. Blisters heal followed by dystrophic or hypertrophic scarring. Formation of Milia (1-4mm
white papules) occur because of damage to hair follicles. 2, 5
There are two main subtypes of DEB, Dominantly inherited DEB and Recessively inherited DEB.

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Dominant DEB
The disease starts at birth or during infancy with generalized blistering as a common presentation. As
the patient gets older, localized blistering is present on traumatised areas such as the knees, sacrum
and acral surfaces. A more common type has an acral distribution and minimal oral or tooth
involvement. Another type of DEB has more blistering, scar like papules on the trunk called
albopapuloid lesions. Dystrophic or absent nails are common in dominantly inherited dystrophic
epidermolysis bullosa. 2, 5
Figure 8 shows hypertrophic scarring often seen in generalised DDEB with acral distribution.

Figure 8 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.
Recessively inherited DEB
The intermediate and localized subtypes have clinical manifestations similar to the dominantly
inherited forms of DEB. localized cutaneous lesion are of pretibial or acral distribution. The less
severe subtypes often involve the nails with less mucosal involvement.2, 5

Severe generalized recessive epidermolysis bullosa shows generalized blistering at birth and
extensive dystrophic scarring that is prominent on the acral surfaces. The extensive dystrophic
scarring can produce pseudosyndactyly (mitten-hand deformity) of the hands and feet. Flexion
contractures of the extremities are increasingly common with age due to scarring. Nails and teeth
also are affected. 2, 5

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Figure 9, the image below, shows pseudosyndactyly of both hands in a patient who has severe
generalised recessive DEB.

Figure 9 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.

Figure 10- RDEB generalized erosions-from the archive of Colentina Clinical Hospital –Children Dermatology
Department.

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Involvement of internal mucosa can result in oesophageal strictures, urethral and anal stenosis,
phimosis and corneal scarring. Malabsorption commonly results in a mixed anaemia due to lack of
iron absorption. Overall malnutrition may cause failure to thrive. Patients with severe recessively
inherited epidermolysis bullosa who survive to childhood are at significant risk of developing
aggressive squamous cell carcinoma (SCC) where there are chronic erosions. 2, 5
Figure 11 shows tiny white papules called milia in an erythematous plaque on the patient’s knee. This
is a typical characteristic in patients who have Dystrophic EB.

Figure 11 from FINE, JO-DAVID. “Inherited epidermolysis bullosa.” Orphanet journal of rare diseases 5.1 (2010): 12.
1.3.4 Kindler Syndrome
In Kindler’s syndrome, there are prominent cutaneous manifestations. These include, fragile skin with
trauma or caused by sunlight, photosensitivity, which can lead to erythema and burning. Skin atrophy,
poikiloderma which is patches of hypo- and hyperpigmentation all over the skin, and
pseudosyndactyly can also occur patients with Kindlers syndrome. This condition also affects the
nails causing dystrophy or atrophy to occur. 8
As well as cutaneous involvement, there is also mucosal involvement. Common features include
gingivitis, hypohidrosis, oesophageal stenosis and ulcers of the buccal mucosa. 8
1.4 Diagnosis
When epidermolysis bullosa is suspected, the best approach is to obtain two biopsy specimens.
Analyse one specimen using electron microscopy and the other using immunofluorescent
microscopy. 2

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1.4.1 Skin biopsy for immunofluorescent mapping
A small sample of affected skin is removed and examined with a microscope and reflected light to
identify the layer or layers of skin involved. This test also identifies whether the proteins needed for
skin growth are functioning. 7
1.4.2 Immunofluorescent microscopy
This study can provide information on the level of the blistering. Obtain a biopsy specimen at the
edge of a fresh blister for optimal results.
Immunomapping done using antibodies and binding them to a hemidesmosomal antigen such as
BP230 can be obtained from a patient with bullous pemphigus and an antibody to a lamina densa
protein such as type IV collagen can be used to distinguish between the types of EB. In epidermolysis
bullosa simplex, both BP230 and type IV collagen are localize to the floor. In junctional
epidermolysis bullosa, BP230 localizes to the roof of the blister, while type IV collagen localizes to
the floor. In dystrophic epidermolysis bullosa, both antigens localize to the roof of the blister. 2, 13
In addition to providing information about the level of the skin separation, immunofluorescent
microscopy can be useful in providing information on the underlying molecular defect. 2
The image below is a photomicrograph showing normal expression of laminin 332 in the control
skin (a), complete absence of staining for laminin 332 in JEB-H. (b) Image C shows normal
expression of type VII in the control skin (c) and complete absence of staining in RDEB (d) 13

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Figure 12 – from RAO, RAGHAVENDRA, ET AL. “Immunofluorescence antigen mapping for hereditary
epidermolysis bullosa.” Indian Journal of Dermatology, Venereology, and Leprology 78.6 (2012): 692.

1.4.3 Genetic testing.
Genetic testing is used to confirm the diagnosis because most forms of epidermolysis bullosa are
inherited.
The localization of the mutation is important for assessing the evolution and prognosis of the EB
subtype. The exact localization of the mutation is also important for the carrying out of gene therapy.
Prenatal diagnosis in affected families is possible only by knowing the mutation. The investigation is
done with cortical villus material or amniocentesis. Identifying a new mutation, supports genetic
research studies.
A small sample of blood is taken and sent to a lab for analysis. Analysis of a mutation can be done
after immunofluorescent microscopy. This is the last step in finding out about the molecular defect
causing EB. DNA is extracted from blood of the patient and family members. Initial mutation
screening is completed by restriction fragment-length polymorphism analysis, hotspot analysis, and
direct DNA sequencing. 2, 7
1.4.4 Prenatal testing.
Families with a history of epidermolysis bullosa are recommended to have prenatal testing. DNA for
prenatal diagnosis can be obtained as a chorionic villi sample from the ninth week of gestation
onwards. Alternatively, amniotic fluid taken after the eleventh week can provide the necessary DNA.
2, 7
1.4.5 Blood tests
Complete Blood count (CBC) with iron in patients with severe EB is important especially in
recessively inherited DEB. 2
There are periodic examinations that need to be carried out, these are: CBC, renal function tests such
as BUN, creatinine, electrolytes, liver function tests, albumin, iron, inflammation markers, serum
folate, B12, vitamin D metabolites, urinalysis. A culture from the wounds is recommended to check
for bacterial infection. There are also recommended periodic clinical tests such as: eye examination,
urography for urethral strictures, cardiac examination, DEXA scanning for osteoporosis. 2, 7

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1.4.6 Imaging tests
Using endoscopic methods, GI dysfunction can be assessed. Oesophageal strictures associated with
JEB and DEB or the pyloric atresia associated with a rare form of junctional epidermolysis bullosa
can be seen. 2
1.5 Management/Treatment
There is currently no cure for EB, however there are several treatments used to manage the symptoms
of EB and to prevent life threatening complications. The treatment varies depending on the type of
EB and the complications which an individual has the risk of developing. 2, 8
The objectives in caring for all EB patients are to prevent blisters from forming by using protective
padding on the skin and to avoid trauma. Another objective is to prevent secondary infection. This
is carried out by using sterile synthetic non-adhesive hydrocolloid dressings. 2, 8
Patients with EB subtypes that are high risk for specific extracutaneous complications need careful
surveillance for their occurrence, and appropriate interventions need to be applied such as medical,
surgical, dental, nutritional, and psychological. 2, 8
The patient’s assessment should include, besides the general exam, the examination of all the skin
and the mucous membranes. Clinical evaluation and quality of life scores for EB are:
1. BEBS (Birmingham Epidermolysis Bullosa Score),
2. EBDASI ( Epidermolysis Bullosa Disease Activity and Scarring Index),
3. QOLEB (Quality of Life in Epidermolysis bullosa questionnaire),
4. cDLQI (Children’s Dermatology Life Quality Index)
1.5.1 Medical treatment
Wound care
In order to prevent complications such pseudosyndactyly, the patient’s digits are often wrapped
tightly with bandages at night. If hand deformities have already occurred then surgical degloving
procedures can be carried out to avoid this. 4
Patients who had EB have slower wound healing especially in JEB. This is because of the defect in
laminin-332 which is a protein that is involved in keratinocyte adhesion and migration. 4
To speed up the healing, protecting the patient’s skin is important. As a result, Patients with severe
epidermolysis bullosa require a lot of wound-care supplies, such as plain petroleum gauze, non-

26

adhering gauze, petroleum jelly, antibiotic ointment, and self-adhering gauze. Antibiotic treatment is
added to prevent infection. 2
Infection
Infections occur easily in patients who have EB for several reasons. Firstly, due to the loss of stratum
corneum barrier, they are more exposed to bacteria in the environment and the accumulation of serum
and moisture that occurs on the skin enhanced the growth of bacteria. Secondly, patients with severe
cases of EB have immunologic abnormalities which lowers their resistance to bacterial infections.
This puts these patients at high risk of being infected by bacteria such as staphylococcus aureus and
streptococcus pyogenes. For this reasons, the use of non-adhesive dressing and topical antibiotics are
required as treatment for these patients. 2, 4
Tumours
Chronic cutaneous lesions in EB can lead to squamous cell carcinoma. It occurs more often in patients
who have the generalised recessive DEB and junctional EB subtypes. This can occur as early as the
second decade of life in severe cases. This is often treated surgically. 2, 4
Systemic medical treatment
Systemic medication possibilities tried to treat EB patients include:
? Cyclosporine – clinical benefits in the treatment of DEB when prescribed is to prevent graft
rejection in a child with DEB. long term use of ciclosporin cannot be recommended because
it increases the risk of skin malignancy in RDEB.
? Trimethoprim- anti-inflammatory effects based on diminished chemotaxis of
polymorphonuclear leukocytes, modification of complement pathways and inhibition of
MMPs
? Anti TNF alpha
? Phenytoin is a collagenase activity inhibitor, but a multi-centre randomised, placebo-
controlled, double blind, cross over study of phenytoin in RDEB, from 1992 showed no
significant therapeutic effect
? Minocycline there are no large clinical trials for validation in RDEB
? Epigallocatechin-3-gallate is a green tea extract that regulates the activity of MMP in vitro; in
2016 a multicentre, randomised, crossover, double blind, placebo controlled clinical trial in
17 RDEB individuals failed to demonstrate statistical significance
? Mycophenolate mofetil

27

In EB, there is an occurrence of complication in the gastrointestinal (GI) tract, the eyes and the trachea
and the oral cavity.
GI
Oesophageal lesions causes by EB can be are managed in several ways. Management is done by using
oral steroid elixirs to reduce the symptoms of dysphagia. Also, if oral candidiasis is present, an anti-
candidal medication is helpful. In order to maintain adequate intake of nutrients by mouth, some
patients with EB are given supplements via gastrostomy. This is to prevent severe malnutrition, a
complication of EB. 2, 4, 6
Eyes
Patients with EB simplex can experience recurrent blepharitis in one or both eyes along with bullous
lesions of the conjunctivae. Chronic blepharitis can result in exposure keratitis. Moisture chambers
and ocular lubricants are used for management. 2
Patients with Junction EB can experience corneal scarring, corneal ulcerations, obliteration of tear
ducts, and eyelid lesions. Corneal erosions are treated supportively with application of antibiotic
ointment and use of cycloplegic agents to reduce ciliary spasm and provide comfort. 2
Using tape to patch the eye should be avoided because of the high risk of blistering of the skin under
the adhesive. 2
Oral cavity
Good dental hygiene is essential for patients with epidermolysis bullosa. Patients with JEB and DEB
develop dental cavies because of the enamel defects. The oral mucosal involvement occurs in severe
forms of junctional EB and dystrophic EB. Normal saline rinses can help gently clean the mucosal
surfaces. Patients should avoid using alcoholic mouthwashes. 2
1.5.2 Surgical Treatment
This method of treatment is often used to treat complications of EB such as pseudosyndactyly and
SCC. Surgery is also used to correct non-cutaneous complications of EB such as oesophageal
strictures, ulcers and various types of lesions on the oesophagus. 2, 4
Surgical treatment of SCC
Squamous cell carcinoma is a common complication in patients diagnosed with RDEB after puberty.
SCC tend to arise in non-healing areas. Surgical excision of the carcinoma is used to treat SCC. This
can be done via Mohs surgery or non-Mohs surgery techniques. 2, 5

28

Allografts
Allografts are tissue grafts from a donor of the same species as the recipient but not genetically
identical. These allografts are eventually rejected by immunocompetent hosts such as patients with
epidermolysis bullosa. These tissue grafts have been useful in facilitating the healing of the skin
lesions in persons with epidermolysis bullosa and in improving the overall quality of life of these
patients. These allografts work by producing cytokines that facilitate the wound healing process and
stimulate reepithelialisation of the patients’ wounds. 2, 4
Laser therapy
This treatment is often used to treat Kindler Syndrome. Telangiectasia (widened capillaries) and
poikiloderma (variety of shades of pigmentation in the skin) are complications of this form of EB.
This condition can be treated with pulsed-dye laser therapy. 8
Surgical treatment of pseudosyndactyly
Mitten deformity of the hand is a common occurrence in patients with DEB. Repeated episodes of
blistering and scarring eventually leads to fusion of the web spaces between the digits. As a result,
fine manipulative skills are lost. Surgical procedures can correct this deformity, but there is a high
rate of recurrence. Usually the dominant hand has earlier recurrence. Recurrence appears to be
delayed by the prolonged use of splinting in the interphalangeal spaces at night. 2, 4
Figure 13 – RDEB patient after hand surgery; from the archive of Colentina Clinical Hospital Children Dermatology
Department

29

G.I. management
In certain types of EB such as JEB and RDEB, oesophageal strictures occur which can cause
dysphagia in patients. As a result, surgical techniques are used to achieve oesophageal dilatation.
Removing the oesophageal strictures by colonic interposition is effective in cases of advanced
disease. Recurrence of dilatation is common in these patients. Gastrostomy tube insertion can be also
used to provide nutrition to individuals with oesophageal strictures. 2, 5
1.5.3 Clinical Trials
1.5.3.1 Regeneration of Epidermis with Stem cells
In 2015, research was carried out to find a new way to treat junctional Epidermolysis Bullosa. This
is the type of EB is often lethal and patients with this condition often have a short life expectancy.
This experiment was carried out on a 7 year old patient with JEB who all previous methods of
treatment had failed. In this experiment, plastic cultured skin grafts were made using transgenic
epidermal stem cells and used on a patient who had junctional EB. They made these cultures by taking
some skin from the patient’s left inguinal region which had no lesions. The transgenic epidermal
grafts created from the patient’s healthy skin were normal and was used to cover the lesions caused
by JEB. This treatment has been previously used to treat patients with life threatening burns. 10
The transgenic epidermal cultures generated an entire functional epidermis in a patient with JEB. This
is consistent with the use of keratinocyte cultures for decades to successfully treat victims of life-
threatening burn. 10
In conclusion, transgenic epidermal stem cells can regenerate a fully functional epidermis virtually
indistinguishable from a normal epidermis, in the absence of related adverse events so far. The
different forms of epidermolysis bullosa affect approximately 500,000 people. The successful
outcome of this study paves the way for gene therapy to treat other types of epidermolysis bullosa
and provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and
gene therapies. 10
1.5.3.2 Granulocyte Colony-stimulating factor for EB treatment
A clinical trial in 2015 showed an acceleration in the wound healing when G-CSF is used to treat the
patients. There was evidence of reduction in lesion size and reduction in blister and erosion formation.
14

30

2 Ichthyosis
Ichthyosis is a congenital skin disorder that causes the skin to become dry and scaly and appear to
look like fish scales. The prefix “ichthy” is taken from the Greek root for the word fish. Each year,
more than 16,000 babies are born with some form of ichthyosis. In patients with ichthyosis, the barrier
function of the skin is compromised. It has a decreased ability to protect against bacterial, chemical,
and mechanical assault and to prevent trans-epidermal water loss. In infancy, the disrupted skin
barrier can be dangerous, at times life-threatening. This is due to the increased risk of infection
secondary to impaired skin integrity. This is also dangerous because of increased metabolic demands
because of increased epidermal turnover and the increase of evaporative heat and water loss. 15, 16
2.1 Epidemiology
In the US, Ichthyosis vulgaris is the most common form of Ichthyosis and is an autosomal dominant
trait with an incidence of 1 case per 300 population. Epidermolytic hyperkeratosis is an autosomal
dominant disorder with an incidence of 1 case per 300,000 population. Lamellar ichthyosis, a more
severe form of dermatosis, has an incidence of 1 case per 300,000 population. X-linked recessive
ichthyosis has an incidence of 1 case per 6000 males. 15
There is a higher prevalence of X-linked Ichthyosis as compared to ichthyosis vulgaris in Mexico. 15
In the United Kingdom, the incidence of ichthyosis vulgaris was reported to be 1 case per 250
population in a study population of 6501 healthy school children. The incidence of X-linked recessive
ichthyosis was 1 case in 6190 males. 15
In a Danish population study, the incidence of X-linked recessive ichthyosis was 1 case per 2000
males. In a Danish study, Epidermolytic ichthyosis had a prevalence of 1 in 350,000, with a high
percentage of de novo mutations (75%). 15
In southern coastal Italy, the frequency of X-linked recessive ichthyosis was estimated at 1.98 in
10,000 males.
In China, Ichthyosis vulgaris has a prevalence of 2.29%. 21
Mortality/Morbidity
Men with ichthyosis vulgaris have an increased risk of testicular cancer. In addition, an increased
incidence of testicular maldescent, cryptorchidism, decreased sperm count or motility leading to
infertility. Testicular cancer has been reported in patients with X-linked recessive ichthyosis.

31

X-linked recessive ichthyosis is much more prevalent in males. It is caused by a deficiency of STS.
Because this enzyme plays an important role in androgen metabolism, men with this disease don’t
get androgenetic alopecia. 21, 23
2.2 Pathology
There are several types of ichythyosis, most types are inherited and a few are acquired 23

Table V from Fitzpatrick dermatology in general medicine chapter 47
The table above (Table V)23 –Fitzpatrick dermatology in general medicine chapter 47 is a summary
of the inherited autosomal dominant and semidominant types of ichthyosis and their characteristics.

32

The main types of ichthyosis are
? X-linked Ichthyosis
? Ichthyosis Vulgaris
? Harlequin Ichthyosis
? EHK – Epidermolytic hyperkeratosis (bullous ichthyosiform erythroderma)
? Lamellar ichthyosis
? Acquired Ichthyosis
2.2.1 Ichthyosis Vulgaris (IV)
This is the most common form of ichthyosis and is relatively mild. This type of ichthyosis manifests
during the first year of life. It is an autosomal semi-dominant skin disorder caused by a mutation of
the gene coding for profilaggrin. This means that those who have the mutation on one profilaggrin
allele (heterozygous) do present with symptoms but they are often mild. Patients who have the
mutation on both profilaggrin alleles will present with a more severe form for IV. 15, 21, 23
Scaling is most prominent over the trunk, abdomen, buttocks, and legs. There are two loss-of-function
mutations in the coding of the filaggrin (filament aggregating protein) gene identified in both
ichthyosis vulgaris and atopic dermatitis. This shows that there is an association between ichthyosis
vulgaris and atopic dermatitis. 15
Keratohyaline synthesis is affected because of the profilaggrin mutation. Profilaggrin is an epidermal
protein that normally functions as a barrier molecule against environmental allergens, water loss, and
infection. This makes patients who have ichthyosis vulgaris more susceptible to infections. 15
2.2.2 X-Linked Recessive Ichthyosis
In this type of ichthyosis, generalized scaling is present at birth. This scaling occurs the most in the
extremities, neck, trunk, and buttocks. The flexural creases may be involved. palms, and soles are not
affected. This condition is mostly found in males. Females are often carriers of this condition. This is
because it is X-linked recessive meaning for a female to have this condition, both of her X
chromosomes would have the mutation. Whereas males only have one X chromosome and if that one
X chromosome has Ichthyosis then the male will have X-linked ichthyosis. 15, 23
Irregular stromal corneal opacities that are located anterior to the Descemet membrane are found in
16-50% of male patients, and this finding may be used to distinguish this form of ichthyosis from all

33

other forms. Approximately 25% of female carriers have minor corneal opacities. The corneal
opacities are not known to affect visual acuity. 15
2.2.3 Harlequin Ichthyosis (HI)
Harlequin ichthyosis is a congenital disorder. Infants with this condition are often born prematurely.
They are born with massive shiny plates of stratum corneum which are separated by deep red fissures.
These plate and fissures form a geometric pattern like Harlequin clown costumes. The skin barrier is
severely compromised therefore, neonates are more prone to sepsis, dehydration, and impaired
thermoregulation. 17, 23

Figure 14 shows a new born with thick plates of stratum corneum seen in harlequin ichthyosis from FLECKMAN P,
DIGIOVANNA J J. “Ichthyosis” Wolff Klaus et al, Fitzpatrick’s dermatology in general medicine, 7th ed, New York,
McGrawhill Medical,2008:401-23
2.2.4 Epidermolytic hyperkeratosis (bullous ichthyosiform erythroderma)
This type of Ichthyosis is an autosomal dominant disorder. Is caused by a mutation in the KRT1 and
KRT10 genes for keratin. EHK is characterised by hyperkeratosis and blistering. EHK presents as
mild generalized erythroderma which is present at birth. Bullae formation often occurs, if infected, it
causes a foul skin odour. Erythroderma fades during infancy while the grey, waxy scales remains.
They are particularly prominent in the flexural creases. 15, 21

34

2.2.5 Lamellar ichthyosis
Lamellar ichthyosis is a rare, autosomal recessive type. It is a genetically heterogeneous skin disease
caused by mutations involving multiple genetic loci. Lamellar ichthyosis can be seen clinically as
dark, armour-like scales. There are two types, type 1 and type 2. 15, 21
Type 1 maps to band 14q11.2 and is caused by mutations in the gene for keratinocyte
transglutaminase 1, an enzyme responsible for the assembly of the keratinized envelope. 15, 21
Type 2 is clinically indistinguishable from type 1, maps to band 2q33-q35. 15
In classic lamellar ichthyosis, children with the disease are referred to as collodion babies and are
covered at birth by a thickened membrane that eventually shed. The scaling of the skin involves the
whole body with no sparing of the flexural creases. 15, 21

Figure 15 from FLECKMAN P, DIGIOVANNA J J. “Ichthyosis” Wolff Klaus et al, Fitzpatrick’s dermatology in
general medicine, 7th ed, New York, McGrawhill Medical,2008:401-23
The image above, (figure 15) shows typical lamellar ichthyosis phenotype with the large, brown,
plate-like scales. 23
2.2.6 Acquired Ichthyosis
Acquired ichthyosis usually occurs in adults. It manifests as small, white, fishlike scales that
frequently are concentrated on the extremities. 15

35

This form of ichthyosis may be associated with internal neoplasia such as; Hodgkin lymphoma,
leukaemia; systemic illness such as sarcoidosis, HIV infection, hypothyroidism, chronic
hepatitis, malabsorption and bone marrow transplantation. This type of ichthyosis can also be caused
by taking medications that interfere with the sterol synthesis in epidermal cells, for example, nicotinic
acid. 15
2.2.7 Sjogren-Larsson Syndrome
Sjögren-Larsson syndrome is an autosomal recessive condition that comprises ichthyosis, spastic
diplegia, tetraplegia, pigmentary retinopathy, and mental retardation. These neurologic
manifestations tend to manifest in the first two to three years of the patients life. SL syndrome is
caused by mutations in the gene for fatty aldehyde dehydrogenase. 15, 21, 23
2.3 Clinical aspects
Ichthyosis not only affects the skin, but it affects parts of the eyes such as the retina, cornea,
conjunctiva and eyelids. 15
2.3.1 Cutaneous
Ichthyosis vulgaris
In this condition, your skin’s natural shedding process is impaired. The growth rate of skin is normal
but the shedding is slower. This causes chronic, excessive build-up of the protein in the upper layer
of the skin. Symptoms include:
? Dry, scaly skin
? Tile-like, small scales
? Scales coloured white, dirty grey or brown — with darker-coloured scales typically on darker
skin
? Flaky scalp
? Deep, painful cracks in your skin 19
The scales usually appear on your elbows and lower legs, the scales are especially thick and dark over
your knees. Symptoms usually worsen or are more pronounced in cold, dry environments and tend to
improve in warm, humid environments. 19

36

Sjogren-Larson syndrome
It appears at birth, lesions can range from fine scales to generalised hyperkeratosis. The thickened
areas ae yellow to brown in colour and have a lichenified appearance. The most affected areas are
the back of the neck, lower abdomen and flexures. 23
Epidermolytic hyperkeratosis (bullous ichthyosiform erythroderma)
This disease presents at birth with blistering, redness and peeling. As the condition develops, the
stratum corneum layer of the skin is extremely thick, vacuolar degeneration of the upper part of
the epidermis occurs. This can be seen under an electron microscope. This type of ichthyosis has
a strong odour this could be caused by the superinfection that occurs due to mixed flora. These
lesions are most prominent in the palmar and plantar regions and the flexures. 23
X-linked recessive Ichthyosis
In this type of ichthyosis, generalized scaling is present at birth. This scaling occurs the most in the
extremities, neck, trunk, and buttocks. The flexural creases may be involved. Palms, and soles are
not affected. 15, 23
Lamellar Ichthyosis
Patients with this type are often born with a collodion membrane. Lamellar ichthyosis can be seen
clinically as dark, armour-like scales which are arranged in a mosaic pattern. These scales appear
the largest on the lower limbs. 23
Harlequin Ichthyosis
Infants born with this condition have massive, thick, shiny plates of stratum corneum which are
separated by deep red fissures. These plate and fissures form a geometric pattern like Harlequin
clown costumes. These infants are often poorly developed as they can be born with their ears
missing. 23

2.3.2 Ocular and periocular manifestations
Conjunctiva
? Keratinization and thickening secondary to ectropion
Cornea
? All forms of Ichthyosis

37

o Exposure keratitis secondary to ectropion
o Recurrent corneal erosion
o Band keratopathy
o Microphthalmos
o Anterior chamber cleavage syndrome
o Enlarged corneal nerves
o Stromal vascularization
? Lamellar ichthyosis
o Unilateral megalocornea lamellar ichthyosis
? X-linked Ichthyosis
o Pre-Descemet membrane opacities
? Ichthyosis Vulgaris
o Salzmann nodules
The image below (figure 16) shows a cross section cornea under a slit lamp examination. The
opacities appear white. 23

Figure 16 – from FLECKMAN P, DIGIOVANNA J J. “Ichthyosis” Wolff Klaus et al, Fitzpatrick’s dermatology in
general medicine, 7th ed,……, McGrawhill Medical,2008:401-23
Eyelids
? Ectropion (lamellar ichthyosis)
? Blepharitis
? Meibomian gland absence (rare)

38

? Trichiasis
? Madarosis
? Lacrimal puncta absence
Retina
? Coloboma
? Retinitis pigmentosa
? Maculopathy
? Tortuous vessels
2.3.3 Complications
The Skin is your body’s barrier from the environment. It holds moisture inside and keeps out bacteria
and other invaders that might make you sick. Ichthyosis causes excessive scaling causing you to lose
some of the protective layer. 20
Scaling can lead to complications such as:
? Infections
? Dehydration
? Blocked sweat glands, which can lead to overheating
? Slow hair growth from scales on the scalp
? Burning more calories, because the skin has to work harder to turn over cells 20
2.4 Diagnosis
2.4.1 Laboratory Studies
Congenital Ichthyosis
In congenital ichthyosis disorders, histopathology, electron microscopy, and sections of skin biopsy
specimens are required to determine which type of Ichthyosis the patient has. 15
Skin biopsy is used to diagnose Ichthyosis vulgaris, X-linked recessive ichthyosis, Epidermolytic
hyperkeratosis and lamellar ichthyosis.
STS or steroid sulfatase activity is a test used to measure cholesterol sulfate levels. This is done is
varies types of Ichthyosis especially X-linked recessive ichthyosis.

39

Genetic testing is used to test for deletions in genes. This includes the STS gene on band Xp22.3
found in X-linked recessive ichthyosis. This is also used to diagnose Lamellar Ichthyosis by looking
for mutations in the gene for transglutaminase 1. Keratin gene studies are carried out to diagnose
Epidermolytic hyperkeratosis. 15, 21

To diagnose Sjögren-Larsson syndrome, NAD oxidoreductase assay is carried out. 15
Acquired ichthyosis
Acquired ichthyosis in adult patients is often an indication of various autoimmune disorders or
malignancies. Acquired ichthyosis could be a sign of an HIV infection. The lab tests are to find out
if the patient has an autoimmune condition or a malignancy which is causing ichthyosis. 15, 16, 17
? HIV testing
? CBC count. This is to check for syndromes such as leukaemia and myelodysplastic
syndromes.
? Thyroid function tests to check for hypothyroidism.
? Serum angiotensin converting enzyme and lysozyme lab test to check if the patient has
sarcoidosis.
? Chest radiography to check for sarcoidosis, lymphoma, HIV and tuberculosis.
? Serum antinuclear antibody (ANA), anti-double stranded DNA (dsDNA) antibody,
anticentromere antibody (ACA), and anti-Scl-70 antibody- These lab tests are to find out if
the patient has systemic lupus erythematosus (SLE) and systemic sclerosis.
2.4.2 Imaging Studies
In congenital ichthyosis syndromes, ultrasonography scanning shows excessive intra-amniotic debris
and polyhydramnios. Using ultrasonography scanning during pregnancy, foetal foot length may and
indication for harlequin ichthyosis in the second trimester. The echography could show a persistently
open mouth, dense amniotic fluid, and fixed flexion of the extremities.
2.5 Management/Treatment
There is no cure for ichthyosis, however, with medical and surgical treatment, the symptoms can be
managed effectively and the quality of life for the patient can be improved.

40

2.5.1 Medical care
Current treatments for ichthyosis focus on the use of Keratolytics, hydration and lubrication of the
skin. All three agents mentioned are needed to remove scales from the skin and retain moisture. 23
Systemic
Oral retinoids reduces scaling, discomfort, and disfigurement. When the drugs mentioned below are
discontinued, ichthyotic skin reoccurs, so long-term use is necessary. Oral retinoids include:-
? Etretinate (1 mg/kg/d)
? Isotretinoin (2 mg/kg/d)
Retinoids can cause side effects such as dry mouth, upset stomach and weakened bones. 15, 20
Antibiotic therapy is used to treat chronic bacterial infections that occur as a complication of
ichthyosis. 15
Patients with Sjögren-Larsson syndrome have a deficiency of fatty aldehyde dehydrogenase
(FALDH). Bezafibrate, a hypolipidemic drug, induces the activity of FALDH in these patients.
Mechanical scale removal
Mechanical removal of scales after bathing is more efficient than the use of keratolytics. Microfiber
household towels, pumice stones, and special silk from China are most effective. Scale removal is
done by repetitive gentle rubbing can be achieved in the bathtub once the patient has soaked for 30
minutes. The process lasts about an hour if the entire body is affected. This should be done
frequently, from two times a week up to twice a day depending on the severity. A simple cream
must be applied immediately after getting out of the bathtub. 22
Topical
Topical cyclosporine A 2% is given 3 times daily to treat deep stromal keratitis. To prevent cicatricial
ectropion in lamellar ichthyosis, a humidified atmosphere combined with the use of topical
moisturizing agents is beneficial.
Petrolatum ointment and 10% urea cream can be applied to the eyelid skin several times a day to help
prevent skin contracture. 15
Salicylic acid 2% and retinoic acid 0.1% ointments are also used but local irritation may limit their
frequency of use. 15, 23

41

Calcipotriene ointment is used to treat only hyperproliferative forms of ichthyosis. It can cause
hypercalcaemia in congenital conditions.
Pimecrolimus 1% is an immunomodulating agent used in the treatment of atopic dermatitis. It is also
effective in treating patients with Netherton syndrome. ‘Immunomodulation effects are similar to
tacrolimus but without evidence of lipophilic adverse effects’. 15
Keratolytics such as salicylic acid, urea and ?-hydroxyl acids such as lactic acid are used to soften
the skin and remove the scales from the skin. Urea is effective because it can bind to water, therefore
increasing moisture. 23

Table VI – Traupe, Heiko, and Walter HC Burgdorf. “Treatment of ichthyosis–There is always
something you can do! In Memoriam: Wolfgang Küster.” Journal of the American Academy of
Dermatology 57.3 (2007): 542-547.
The table above 22 shows some guidelines to consider when treating children with congenital
ichthyosis in different stages of their lives from neonatal up till childhood. This includes topical
treatments such as application of urea cream and emollients. It includes checking electrolyte levels
and bathing techniques.

42

3. Netherton syndrome
Netherton syndrome is an autosomal recessive disorder caused by mutations in the SPINK5 gene.
This condition is often seen at birth with generalized redness called erythroderma. Other symptoms
are hair shaft abnormalities, most commonly trichorrhexis invaginata (bamboo hair), atopy and
elevated IgE levels. Hair shaft abnormalities can be particularly helpful in distinguishing Netherton
syndrome from other disorders with similar clinical presentations. 15, 16, 23
3.1 Epidemiology
The frequency of Netherton syndrome is not known. Approximately 200 cases of Netherton syndrome
have been reported. The incidence of this condition may be as high as 1 case in 50,000. This condition
occurs more in girls than boys. Children affected by Netherton syndrome present with erythroderma
within 1-6 weeks of birth. 18
3.2 Pathology
Netherton syndrome is caused by a mutation on band 5q32, specifically encoding
for LEKTI (Lymphoepithelial Kazal-type related inhibitor) which is a serine protease inhibitor. 15
The Netherton syndrome is an autosomal recessive disorder due to mutations of both copies of
the SPINK5 gene on band 5q31-32. Each SPINK5 mutation leads to a different length of LEKTI
protein. This causes phenotypical symptoms such as atopic dermatitis, growth retardation, skin
infection, increased stratum corneum protease activities and elevated kallikrein levels in the stratum
corneum. 18
Trichorrhexis invaginata or bamboo hair, is a hair shaft abnormality that occurs as a result of a
keratinizing defect of the hair cortex. Incomplete conversion of the sulfhydryl –SH group onto S-S
disulfide bonds in the protein of the cortical fibres leads to cortical softness. As a result, there is
invagination of a fully keratinized distal hair shaft into keratinized proximal hair shaft. This results
in a distinctive ‘ball and socket’ hair shaft deformity. The hairs that are affected are brittle leading to
increased breakage resulting in short hairs. 18
3.3 Clinical Aspects
? Colloidial membrane
? Ichthyosis linearis circumflexa – this is a generalised hyperkeratosis and polycyclic and
erythematous plaques
? Hair features (trichorrhexis invaginata)

43

? Atopic diathesis 18
The images below (Figure 17) shows the hair features under an electron microscope. This is called
trichorrhexis invaginata. 23

Figure 17 from FLECKMAN P, DIGIOVANNA J J. “Ichthyosis” Wolff Klaus et al, Fitzpatrick’s dermatology in
general medicine, 7th ed,……, McGrawhill Medical,2008:401-23
3.4 Diagnosis
Netherton syndrome – Hair shaft examination with light and electron microscope 15, 18
3.4.1 Blood
? Serum immunoglobulin E (IgE) levels can be increased often exceeding 10,000 IU/mL.
? Specific IgE antibodies to both environmental and food allergens can be detected.
? Hypereosinophilia
3.4.2 Light microscopy of the hair
Bamboo nodes are seen under the light microscope when examining eyebrows and eyelashes. This is
a sign of trichorrhexis invaginata. Trichorrhexis invaginata is the focal cup-and-ball hair-shaft
deformity. This finding is described as a “golf tee” characteristic. The eyebrows may be the only site
of involvement so should be the specimen of choice. The hair specimen is obtained by clipping. 18
3.4.3 Electron microscopy
Electron microscopy shows trichorrhexis invaginata in 10-30% of clipped hair after the age of 2. The
hair fractures at the invaginated node as it’s the weakest point in the hair shaft. Electron microscopy
can be used to identify these proximal halves of invaginate nodes. This shows a cuplike appearance
where the ball of the distal hair fell out. 18

44

Ultrastructural studies shows distorted lamellar bodies and possibly may lose its lamellar structure in
the stratum corneum 18
3.5 Management/Treatment
Emollients, keratolytics, and antibiotics are the main methods of treatment in Netherton syndrome.
White soft paraffin and liquid paraffin in a ratio of 50:50 are used as topical treatment. 18
? Pimecrolimus 1% – is an immunomodulating agent used in the treatment of atopic dermatitis.
It is also effective in treating patients with Netherton syndrome. 15
? Infliximab – was found to lead to clinical improvement and clearance of ichthyosis linearis
circumflexa in one study.18

45

4.Neurofibromatosis

There are two types of neurofibromatosis, NF1 and NF2.
Neurofibromatosis type 1 (NF1), also called von Recklinghausen’s disease, is a genetic disorder of
autosomal dominant inheritance characterized by the development of multiple benign tumours of
nerves and skin called neurofibromas and areas of abnormal skin pigmentation called cafe-au-lait
spots. Freckling can occur in the axillary region or the inguinal region. These abnormalities are
evident by one year of age and tend to increase in size and number over time. 24, 25, 26
Neurofibromatosis type 2 (NF2), also called central neurofibromatosis is a genetic disorder of
autosomal dominant inheritance characterized by the growth of multiple benign tumours in the
nervous system. The most common tumours that occur in NF2 are vestibular schwannomas or
acoustic neuromas. These growths develop along the cochlear nerve. Tumours that occur on other
nerves are also commonly found with this condition. 27, 28, 29, 30
4.1 Epidemiology
NF1 affects both males and females in equal numbers. NF1 affects all races and ethnic groups equally.
It is estimated to occur in 1 in 2,500 to 3,000 births. NF1 occurs in 1 in 3,000 to 4,000 people
worldwide. (24,26)
NF2 is more rare than NF1. It occurs in 1 in 40,000 people worldwide. 30
4.2 Pathology
4.2.1 NF1
NF1 is caused by a mutation in or deletion of the NF1 gene located on the long arm of chromosome
17. The gene provides instructions for making a protein called neurofibromin acts as a tumour
suppressor, this means that it keeps cells from growing and dividing too rapidly. Neurofibromin is
produced in nerve cells and specialised cells surrounding the nerves such as Schwann cells and
oligodendrocytes. Mutations in this gene lead to production of a non-functional version of
neurofibromin that cannot regulate cell growth and division. As a result, tumours form along the
nerves throughout the body. 25, 26, 30

46

4.2.2 NF2
NF2 is caused by a mutations in the NF2 gene located on chromosome 22. The NF2 gene provides
instructions for making a protein called merlin (also known as schwannomin). This protein is
produced in Schwann cells, which surround and insulate neurons in the brain and spinal cord. Merlin
acts as a tumour suppressor, it regulates the growth and division of cells. This protein is involved in
controlling cell movement, cell shape, and communication between cells. Mutations in the NF2 gene
lead to the production of a non-functional version of the merlin protein. 28
4.3 Clinical Aspects
4.3.1 NF1
Clinical findings first seen in children with NF1 are multiple café-au-lait spots. These can be present
at birth and often increase in size and number throughout childhood. In adults, café-au-lait macules
tend to fade and Neurofibromas tend to develop. Axillary or inguinal freckles appear during childhood
through adolescence. 25
Cutaneous
? Cutaneous tumours called neurofibromas – this are softer than the surrounding connective
tissue. These tumours can protrude just above the skin surface or lie just underneath the skin
surface (figure 18).
? Subcutaneous neurofibromas – these are tumours that arise from the peripheral nerve. These
tumours can occur both under the skin and deep in the viscera. They are generally harder than
cutaneous tumours.
? Plexiform neurofibromas – these are benign tumours on the peripheral nerve sheath. They
have a dark colour and spread under the surface of the skin. They appear in the first few years
of life. These types of tumours can cause disfigurement, blindness, loss of limb function and
organ dysfunction. (figure 20).
? Café-au-lait spots
? Freckles in the underarm or groin.
? Pain from the affected nerves.

47

Figure 18: Café au lait spots and axillary freckles in a 4 years old child- image from the archive of Colentina Clinical
Hospital –Children Dermatology Department.
Eyes
? Optic pathway tumours – tumours in the optic pathway occur in 15% of NF1 cases in children.
They can cause severe vision loss in the patient so regular check-ups are important.
? Optic glioma
? Lisch nodules – these are abnormal pigments on the iris of the eye. They are melanocytic
hamartomas of the iris. These can be seen using a slit lamp. These do not affect the vision of
the patient. 25, 27, 30

48

Figure 19- HSIEH, D. T., L. O. ROHENA, AND A. KAO. “Neurofibromatosis Type 1.” Medscape http://emedicine.
medscape. com/article/1177266-overview (2018).
Image above (figure 19) shows cutaneous neurofibromas on the patient’s back. These are often seen
in adolescents and adults who have NF1. Is rarely seen in children 25

Figure 20 plexiform neurofibroma on right leg from HSIEH, D. T., L. O. ROHENA, AND A. KAO.
“Neurofibromatosis Type 1.” Medscape http://emedicine. medscape. com/article/1177266-overview (2018). (25)

49

The image above (figure 20) shows a plexiform neurofibroma on the right leg of the patient. These
types of neurofibromas can be accompanied by overlying hyperpigmentation or hypertrichosis. 25

Figure 21 from HSIEH, D. T., L. O. ROHENA, AND A. KAO. “Neurofibromatosis Type 1.” Medscape
http://emedicine. medscape. com/article/1177266-overview (2018).
The image above (figure 21) shows Lisch nodule on the iris of the eye under a slit lamp. These do
not affect the vision of the patient. 25
4.3.2 NF2
NF2 do have cutaneous symptoms but they are fewer than in NF1. 29
Cutaneous symptoms
? Cutaneous schwannomas – these are plaque like, slightly raised lesions with hair.
? Café-au-lait macules – they are fewer than in NF1. There are usually no more than 6 macules
on the skin.
? Cutaneous neurofibromas occur, these are identical to the neurofibromas found in NF1. 30
Auditory and other non-cutaneous symptoms
? Hearing loss,
? Tinnitus
? Balance problems associated with vestibular nerve lesions.
? Cranial nerve palsies – due to compression of adjacent nerves secondary to an expanding
vestibular schwannoma.

50

? Posterior subcapsular lenticular opacities would be suggestive of NF2, whereas Lisch nodules
would be diagnostic of NF1. 29, 30
4.4 Diagnosis
4.4.1 NF1
According to the National Institutes of Health (NIH) Consensus Conference in 1987, a clinical
diagnosis of NF1 may be made if patients demonstrate at least two of the following :
? Six or more café-au-lait spots 5 mm or larger before puberty or 15 mm after puberty
? Freckling in the axillary or inguinal regions;
? Abnormal clumps of pigment on the coloured portion of the eye called Lisch nodules.
? Certain abnormalities of bone development in the head such as sphenoid wing dysplasia or
abnormal bowing of bones (pseudoarthrosis).
? Two or more neurofibromas of any type or one plexiform neurofibroma;
? An affected parent, sibling, or child with confirmed NF1. 24
4.4.2 NF2
To clinically diagnose neurofibromatosis type 2 (NF2), an individual has at least 1 of the following
three clinical scenarios :

The first scenario is bilateral vestibular schwannomas, unilateral vestibular schwannoma or any two
from the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular
lenticular opacities.

The second clinical scenario is unilateral vestibular schwannoma and any two from the following:
meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities.

The third clinical scenario is Multiple meningiomas and Unilateral vestibular schwannoma OR Any
two from the following: schwannoma, glioma, neurofibroma, cataract.

51

4.5 Management/Treatment
4.5.1 NF1
There is no cure for neurofibromatosis but there are many ways in which the condition can be
managed. Patients with this NF1 should visit the hospital yearly so that complications of NF1 can be
detected early and treated. Complications of NF1 include scoliosis and optic pathway tumours which
can cause blindness. This is why yearly ophthalmologic examinations and x-rays should be done to
monitor the patient. 30
Café-au-lait spots can be removed with laser therapy. 25, 30
Cutaneous neurofibromas that cause pain, loss of function or directly affect vital organ can be
removed surgically. There is risk of the tumour growing back when removed and there is a risk of
nerve damage. Tumours that have grown quickly should be removed promptly as they may become
cancerous. If the patient complains of pruritus, antihistamines can be given to the patient to reduce
the itching. 27, 30
Plexiform tumours used to be treated by surgical debulking for either cosmetic reasons or to prevent
loss of function in the limbs. Surgical treatment often caused a lot of complications because these
type of tumours are very infiltrative in nature. Plexiform neurofibromas also can grow finger-like
projections along the peripheral nerve making them difficult to remove. For this reason, development
of non-traditional chemotherapy is being studied as a more efficient alternative. The chemotherapy
trials include four drugs which are pifenidone -which is an anti-fibrotic agent, farnesyl transferase
inhibitor, peginterferon alfa-2b and conventional chemotherapy with methotrexate and vinblastine. 30
4.5.2 NF2
There is no cure for NF2, management and treatment and yearly check-ups are important to prevent
possible complications of NF2.
Medical care is required for NF2 patients which consists of routine examinations focusing on
preventing potential complications related to CNS or spinal cord lesions. Annual neurologic
assessment by a neurologist may detect subtle sensory or motor deficits even before the patient is
aware of any difficulties. 29
Management by a team of specialists through a multidisciplinary clinic may provide the most
effective care over time. This is especially important with rapid advances in surgical management,

52

including the use of such tools as stereotactic radiosurgery and auditory brainstem implants (ABIs).
(29)
The main treatment used for NF2 is surgical removal of the tumours. Radiotherapy and chemotherapy
is sometimes used. Small vestibular tumours are treated with stereotactic radiosurgery. This is to
preserve hearing function. Larger tumours are removed surgically even if there is irreversible hearing
loss because of possible brain stem compression or facial nerve palsy. Surgery is also used to remove
cutaneous neurofibromas if they are causing pain or discomfort to the patient. 29
Auditory Brainstem Implants
ABIs are used in some patients with hearing loss caused by vestibular schwannomas. In many cases,
an ABI does not restore hearing but instead improves the patient’s ability to appreciate environmental
sounds and facilitates communication. ABIs do not enable high levels of speech recognition, because
of the cochlear nerve damage in these patients. 29

53

5.Tuberous Sclerosis (TS)
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in
the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems
including the brain, eyes, heart, kidney, lungs and the skin. 31, 32, 38
5.1 Epidemiology
The birth incidence of TSC is estimated to be approximately 1 in 6000. There are approximately two
million people worldwide who have TSC. It occurs with equal frequency in males and females. It
affects all ethnicities and races equally. Hereditary transmissions is evident in one third of patients,
sporadic transmission is evident in two thirds of patients. 31
5.2 Pathology
TSC is caused by mutations in either TSC1, located on chromosome 9 or TSC2, located on
chromosome 16. TSC1 encodes for the protein called hamartin and TSC2 encodes for the protein
called tuberin. Harmatin and Tuberin together form the TSC protein complex. This complex acts
as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway. mTOR plays
a vital role in regulating cell growth, proliferation, autophagy and protein and lipid synthesis.
Patients who has a mutation on the TSC gene tend to have a more severe phenotype. 31, 32, 38
5.3 Clinical Aspects
5.3.1 Cutaneous lesions
? Hypomelanotic macules – are found in over 90% of TSC patients. These are usually detected
in early childhood. These macules typically measure 0.5 to 3 centimetres in diameter. These
lesions are called ‘ash-leaf’ spots.
? Facial angiofibromas – present in 75% of patients. These can be detected at any age but are
more commonly found in adolescent patients. These are 1-3mm in diameter pink to red
papules, they appear hyper-pigmented in darker skinned people. They are usually found in the
centre of the face in the nasolabial folds. These lesions can sometimes occur on the scalp,
forehead and eyelids.
? Pulmonary lymphangiomyomatosis – is often found in adolescent girls or women.
? Renal angiomyolipomas
? Fibrous facial plaque – is often congenital and continues to develop and enlarge during the
patient’s life. This is more common on the forehead, however, this fibrous plaque can be found

54

on the scalp and the cheeks. It is an irregular connective tissue nevus. Fibrous facial plaque
grouped with angiofibromas is a diagnostic feature for TSC.
? Shagreen patch – is a firm irregular plaque ranging from 1-10cm in size. It can have a bumpy
surface due to presence of papules and nodules or it can have an orange peel like surface.
Common locations for this lesion are the lower back and the buttocks.
? Ungual fibromas –
o these are 1mm-1cm in diameter and they form under the proximal nail fold and under
the nail plate.
o The fibromas that form under the proximal nail fold are called the periungual fibroma
and the fibromas that form under the nail plate are called subungual fibroma.
o Periungual fibromas are red papules and nodules that are firm and hyperkeratotic.
They for longitudinal grooves in the nail.
o Subungual fibromas can be seen through the nail plate as red or white oval lesions.
o They can sometimes be seen as red papules emerging from the distal nail plate. The
presence of non-traumatic ungula fibromas is a diagnostic feature for TSC.
? Molluscum fibrosum pendulum also known as skin tags is a multiple fibro epithelial polyp.
These are located on the trunk, neck, axilla and flexures. These polyps are sometimes skin
coloured or hyperpigmented.
? Military Fibromas – These are multiple minute papules located on the neck and trunk.
? Pachydermodactyly – This is benign thickening of the proximal fingers.
? Café-au-lait macules
? Lipomas
? Fibromyolipomas
? Neurofibromas
? Oral fibromas 31, 33
5.3.2 Non-Cutaneous lesions
? Dental pitting
? Intraoral fibromas
? Multiple retinal harmatomas 36, 38

55

Figure 22 – NORTHRUP, HOPE, ET AL. “Tuberous sclerosis complex diagnostic criteria update: recommendations
of the 2012 International Tuberous Sclerosis Complex Consensus Conference.” Pediatric neurology 49.4 (2013): 243-
254.

Figure 23- Ungual fibroma from the archive of Colentina Clinical Hospital –Second Clinic of Dermatology

56

Figure 24 – facial angiofibromas located in the central region of the face from NORTHRUP, HOPE, ET AL. “Tuberous
sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex
Consensus Conference.” Pediatric neurology 49.4 (2013): 243-254.

Figure 25: Facial angiofibromas- image from the archive of Colentina Clinical Hospital Second Clinic of Dermatology

5.4 Diagnosis
5.4.1 Clinical diagnostic criteria
The table below (table VII) shows the clinical diagnostic criteria for Tuberous sclerosis complex. 31

57

Table VII from ORLOVA, KSENIA A., AND PETER B. CRINO. “The tuberous sclerosis complex.” Annals of the
New York Academy of Sciences1184.1 (2010): 87-105.
To be diagnosed TSC, the patient must have two of the major diagnostic symptoms or the patient can
have one major symptom and two minor symptoms.
5.4.2 Genetic Diagnosis
This method of diagnosis distinguishes between a TSC1 or TSC2 pathogenic mutation in DNA from
normal tissue. This method is sufficient to make a definite diagnosis of tuberous sclerosis complex.
A pathogenic mutation is a mutation that inactivates the function of the TSC1 or TSC2 proteins such
as out-of-frame or nonsense mutation, prevention of protein synthesis such a large genomic deletion
is a missense mutation whose effect on protein function can be established by functional assessment.
36
5.5 Management/Treatment
There is no cure for TSC however it can be treated. The goals of treatment is to provide the best
possible quality of life with the fewest complications from the underlying disease process, fewest
adverse treatment effects, and fewest medications. 35

58

5.5.1 Medical care
MTOR kinase inhibitors
Rapamycin is a drug that inhibits mTOR so could be used to treat the internal tumours in TSC.
Sicrolimus (Rapamycin) is an immunosuppressant, which forms an inhibitory complex with the
immunophilin FKBP12, which binds and inhibits the ability of mTOR signalling pathway. 35, 36, 38
5.5.2 Surgical Care
TSC skin tumours are removed by surgical excision.
Surgery is also used to treat the epileptic seizures which are a complication of TSC. These include
focal cortical resection/thermal ablation, corpus callosotomy, or vagus nerve stimulation.
5.5.3 Clinical Trial Sicrolimus (Rampamycin) for TSC treatment
There was a clinical trial completed in 2007 to see the effects of sicrolimus in TSC treatment.
Patients with the tuberous sclerosis complex have mutations in tuberous sclerosis genes resulting in
constitutive activation of the mammalian target of rapamycin (mTOR). The drug sicrolimus
suppresses mTOR signalling so is thought to be useful in treating TSC. 34
This was tested on 25 patients over a 24 month period. Sicrolimus was administered for the first 12
months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed
tomography of lung cysts, and pulmonary-function tests were performed. 34
The results from the experiment shows that Angiomyolipomas regressed during sicrolimus therapy
but tend to increase in volume after the therapy was stopped. Suppression of mTOR signalling might
constitute an ameliorative treatment in patients with the tuberous sclerosis complex. 34

59

Practical part

At Colentina Hospital in the Dermatology department, A computerised database was used to find
patients who have been admitted into the hospital between the years 2000 and 2018. These patients
have been diagnosed with one of the five rare dermatological diseases mentioned in this project.
These are Epidermolysis bullosa, Ichthyosis, Nethertons syndrome, Neurofibromatosis and Tuberous
Sclerosis complex.
With this information, I am going to analyse the data using both descriptive and comparative methods.
6. Objectives
1. Descriptive analysis of the study population considering age, gender and clinical status.
2. Subgroup analyses of the study population according to gender, symptoms status, status of
severity of each of the rare dermatological diseases.
3. Comparative analysis of patients with different rare dermatological diseases and their
subtypes
7. Methods and Materials

7.1 Materials
? Computerized Log sheets of admission and discharged patients between the years 2000 –
2018.
? Patient personal files and data in the dermatology department computer at Colentina Hospital.
? Hospital computer systems and databases
? Laboratory analysis of some of the patients. This includes haematology, urine exam results
and complete blood count.
7.2 Methods
This study is a retrospective and cross-sectional descriptive one of patients who suffer from one of
the five rare dermatological diseases, observing each patient’s age, gender, location of diagnosis,
clinical status at the moment of research and viewing old data regarding past clinical status. The data
was collected from two dermatological departments of Colentina Clinical Hospital, Second Clinic of
Dermatology and the Pediatric Dermatology Department between the dates of September 2017 and

60

June 2018. The study population selected, were all patients presented to the clinics between the years
2000 and 2018 with either a confirmed diagnosis on arrival or a diagnosis during admission.
The main emphasis in the study was to evaluate five rare dermatological diseases found in the
dermatology clinic and how they affect the patients. The information gathering process took place in
the archive departments of hospitals from the computer database.
The cases regarding EB, Ichthyosis, Netherton’s, NF and TSC were dated between the years 2000
and 2018, since this diseases is rare, there was only a small number of patients from each diseases.
There were more patients with EB and Ichthyosis so I did some Clinical and Paraclinical analysis of
patients with these conditions.
The gender of the patients was a data analysis completed to find out if the diseases were more frequent
in males or females and if there are reasons for this. It was also to find out how the diseases affected
the patients based on their gender.
The location of diagnosis and living regions, be it rural or urban also played a major role in the
research, this was important due to several factors:
1. The location could suggest a lack of patient treatment availability and follow-up.
2. The location is key in whether the living population has access to regular healthcare systems,
which may lead to late diagnosis and in-complete treatment.
One of the main including criteria for search was the patient’s age, which were further subdivided
into 6 different age groups: all patients under the age of 18, patients aged 19-29, aged 30-39, aged
40-49, aged 50-59 and aged 60+. I also counted the number of children and the number of adults who
had been diagnosed with the condition between the years 2000 to 2018.
Other search criteria were related with associated pathologies and co-morbidities, trying to assess
whether some different pathologies that arise as complications of certain diseases mentioned such as
nail damage,
All data was searched for using the computer systems of the dermatology department. The
information found was organized in an excel sheets, the data that was collected and stored included:
patient initials, date of admission, patient gender, patient living environment, patient age, patient
definitive main diagnosis, patient’s associated pathologies, patient treatment regimen and other
Commented C1: This sentance seems unfinished

61

relevant information regarding several specific patients. The information collected was used to make
pie charts and bar charts to show my findings.

62

8. Results

There were a total of 79 patients diagnosed with one of the five rare dermatological diseases between
the years 2000-2018. 23 of these patients had Icthyosis, 5 patients had Tuberous Sclerosis Comples,
21 had Neurofibromatosis and 30 of these patients had Epidermolysis Bullosa.

Figure 26
The pie chart above (figure 26) shows that the EB is the least rare dermatological disease in this clinic
with 38% of the seventy nine patients admitted have EB. TSC is the most rare dermaological disease
in this clinic with 6% of the seventy nine patients admitted have TSC. Globally, TSC has a higher
prevalence than EB. TSC occurs in 1 in 6000 people, EB occurs in 1-5 in every 100,000 people, this
varies depending on the country. This could be because TSC is very underreported in Romania.

38%
29%
27%
6%
Rare Dermatological Diseases diagnosed 2000-2018
EBIchthyosisNFTSC

63

8.1 Epidermolysis Bullosa

Types of EB
There are many different subtypes of Epidermolysis Bullosa. There were four types found in the
Colentina clinic in Romania. The pie chart below shows the findings.

Figure 27
This pie chart above (figure 27) shows that Recessive inherited Dystrophic EB is the most common
type of EB found in this clinic with 63% of patients presenting with this form. Acquired EB is the
least common with just 3% of the patients admitted with Epidermolysis Bullosa have this form of
EB. EB simplex is the most common form of EB worldwide. However, in Romania, Dystrophic EB
is the most common type of EB.
63%
27%
7%3%
Types of Epidemolysis Bullosa
Recessive Dystrophic EBEB SimplexJunctional EBAcquired EB

64

Gender Distribution

Figure 28
The pie chart above (figure 28) shows that there are more males diagnosed with EB than females.
The ratio between M:F is 1.2:1. This differs from the epidemiology of the whole of Romania with a
gender ration of M:F 1:1.3. In Romania as a whole, there are more patients with females than males
diagnosed. There could be several reasons for this, this clinic only has 30 patients diagnosed with EB.
According to an article written on ‘Epidemiology of EB in Romania’ in 2015, there were 89 patients
in Romania diagnosed with EB 6. My findings only show some of the patients diagnosed in Bucharest,
Romania as there are several dermatology clinics in Romania.

55%
45%
Gender of EB Patients
MalesFemale

65

Age Distribution

Figure 29
The bar chart above (figure 29) shows that most of the patients diagnosed with EB are eighteen years
old or younger with 21 out of the 30 patients admitted for EB being children. The rest of the age
groups have very few patients. This could be because of the bad prognosis EB has especially in
Junctional EB. This means that majority of the patients in the past wouldn’t make it to adulthood
which is why there are few adults with the condition. Although there is still no cure for EB, treatment
has improved and patients can live longer than they did in the past. Below, there is a pie charge to
show the number of children with EB compared to adults.

Figure 30
There are more children with EB than adults in this clinic with a ratio C:A is 1.7:1.
0
5
10
15
20
25
0-1819-2930-3940-4950-5960+
Number of Patients
Age range
Age Distribution of Patients with EB
63%
37%
Patients with EB
childrenadults

66

Clinical Findings

Figure 31
The bar chart above (figure 31) shows that majority of the patients have nail damage and mucosal
involvement as signs of EB. 21 out of 30 patients which is 70% of the patients with EB present with
nail damage. Mucosal involvement occured in 66.6% of patients presenting with EB.
Microstomia and Oesophagial stenosis are the least frequent complications seen in patients presenting
with EB in this clinic. Both have 8 patients with these complications which is 27%.

0
5
10
15
20
25
Clinical characteristics
yesnono data

67

Clinical Assessment Scores

Out of the 30 patients diagnosed with EB, 23 of these patients were assessed using the BEBS and
DLQI scoring system. DLQI is a dermatological score used to assess the patients quality of life based
on a10 question questionnaire completed by the patient. BEBS is a severity scoring system that covers
all types of EB. The higher the score, the higher the severity. The lower the DLQI score, the less
impact the disease has on the patient’s quality of life.

Figure 32
Majority of the patients have a low score for BEBS. 7 patients have a score ranging between 0-10 for
BEBS. So 30% of the patients have mild forms of EB based on clinical manifestations. 1 patient has
a score of 51-60 and 1 patient has a score of 71-80. There are 0 patients with a score of 61-70 for both
score systems.
Majorit of the patients have a low index value for DLQI. Eight patients have a score of 0-10 for the
DLQI., 35% of these patients have a low score for the DLQI. There are 6 patients with a score of 11-
20 and 5 patients with a score ranging between 21-30. This shows majority of the patients are
impacted by the dieases but not severely. This corresponds with the BEBS score as majority of the
patients have milder forms of EB.
0
1
2
3
4
5
6
7
8
9
0-1011-2021-3031-4041-5051-6061-7071-80
Number of Patients
Score Value
Scores
BEBSDLQI

68

8.2 Ichthyosis
Types of Ichthyosis
There are many different types of Ichthyosis, There were 6 subtypes of Ichthyosis found in the
patients at the clinic. The pie chart below shows the findings.
Figure 33
The Pie chart above (figure 33) shows that Ichthyosis Vulgaris is the most common type of Ichthyosis
with 48% of the patients in the clinic who have Ichthyosis present with this type. Ichthyosis Vulgaris
is the most common type of Ichthyosis globally. (15)
13%
48%
13%
18%
4%4%
Types of Ichthyosis
Lamellar
Vulgaris
Epidermolytic hyperkeratosis (EHK)
Congenital
Associated with Icthyosis
other

69

Gender Distribution
Figure 34
The Pie chart above (figure 34) shows that there are more female patients with Ichthyosis than male
patients. The ratio for F:M is – 1.2:1. The epidemiology of Ichthyosis globally shows there is a higher
mortality and prevalence of Ichthyosis in males than females but more specifically in the X-linked
recessive type of EB. The clinical data doesn’t mention any of the patients having X-linked Ichthyosis
so this could explain why there are fewer males diagnosed with Ichthyosis at Colentina hospital.

45%
55%
Gender of Ichthyosis Patients
MaleFemale

70

Age Distribution

Figure 35
The bar chart above (figure 35) shows that most of the patients diagnosed with Ichthyosis were
eighteen or under. Patients who are 60+ were the group with the second highest number of patients.
There are no patients diagnosed with Ichthyosis in the 40-49 age range.
The pie chart below shows that there are more adults admitted into this clinic with Ichthyosis than
children.

Figure 36
0
1
2
3
4
5
6
7
0-1819-2930-3940-4950-5960+
Number of Patients
Age
Age Distribution of Ichthyosis Patients
30%
70%
Patients with Ichthyosis
childrenadults

71

Location

Figure 37
The pie chart shows that majority of the patients with Ichtyosis live in the Urban areas. This could be
due to the fact that more people live in the urban areas than the rural areas so there is more likely to
be more patients in the urban areas than the rural areas. This could also be because access to medical
care is easier if you live in the urban or city areas than if you live in the rural villages.

32%
68%
Location of Icthyosis Patients
RuralUrban

72

Paraclinical findings
In the clinic, there were laboratory studies carried out on nine out of the 23 patients diagnosed with
ichthyosis. There are certain things that we look for in these tests. Complete blood counts are carried
out, Immunology, Hematology and biochemistry tests are also done. Elevated IgE, Elevated serum
cholesterol and Leukemia are three characteristics we look for in the blood tests of patients diagnosed
with Ichthyosis. The bar chart below shows out findings .

Figure 38
Out of the nine patients laborary tests available, three patients had elevated IgE, three patients had
elevated cholesterol and one patient had increased white blood cell count, this doesn’t necessarily
mean leukemia because to diagnose for leukemia, a bone marrow sample needs to be taken and
assessed.
0
1
2
3
4
5
6
7
8
9
Elevated IgESerum Cholesterol increasedIncreased WBC Count
Paraclinical results in Ichthyosis Patients
yesnounknown

73

8.3 Neurofibromatosis
Gender Distribution

Figure 39
The pie chart above shows that there were more females diagnosed with NF than males with a ration
M:F – 1:1.08. Neurofibromatosis has an equal occurence in both males and females worldwide.

48%52%
Gender Disribution in Neurofibromatosis Patients
MaleFemale

74

Age Distribution

Figure 40
The bar chart above (figure 40) shows the majority of patients diagnosed with NF in this clinic are
between the ages of 30-39, There are no children in the clinic who were diagnosed with NF between
the years 2000-2018. This could be because the skin manifestations of NF get worse over time with
age, it is more mild in childhood so patients may not seek medical help until they are in the adolescent
stage or adults. (16)
0
1
2
3
4
5
6
7
8
9
10
0-1819-2930-3940-4950-5960+
number of patients
Age
Age Distribution of NF Patients

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Location

Figure 41
There are more patients who have Neurofibromatosis in urban areas than in rural areas. The ratio
between R:U is 1:1.08.

48%
52%
Location of Patients with NF
RuralUrban

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8.4 Tuberous Sclerosis
Gender Distribution

Figure 42
The pie chart shows there are more Males with TSC than females in this clinic. The ratio between
M:F is 4:1. Globally, the ratio of males and females with TSC is 1:1 so is equal. This differs a lot to
my findings at the clinic. This could be because there are very few patients that have been diagnosed
with TSC.

80%
20%
Gender Distribution in TSC Patients
MaleFemale

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Age

Figure 43
The bar chart above (figure 43) shows that all the patients diagnosed with TSC are between the ages
of 30-50 years. There are more patients in the 30-39 age range than the 40-49 age range. This could
be due to the fact that there have only been 5 patients recorded with TSC in the last 18 years.

0
0.5
1
1.5
2
2.5
3
0-1819-2930-3940-4950-5960+
Number of Patients
Age
Age Distribution of TSC Patients

78

Location

Figure 44
The pie chart above (figure 44) shows that there are more patients with TSC living in Rural areas than
in Urban areas of Romania. Out of the five dermatological diseases mentioned, this is the only
dermatological condition that has more patients living in rural areas than in urban areas.

60%
40%
Location of TSC Patients
RuralUrban

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9.Discussion
The goal of this project is to visually present the distributions and incidence rates of the rare
dermatological diseases mentioned in this project. Epidermolysis Bullosa has the highest incidence
in the clinic and Tuberous Sclerosis has the lowest incidence of the five diseases.
Epidermolysis bullosa and Ichthyosis both have many subtypes. Epidermolysis has four types and
Ichthyosis has six subtypes found in the dermatological clinic. The most common type of EB was
Dystrophic EB. The most common type of Ichthyosis found in the clinic was Ichthyosis Vulgaris.
The least common type of EB was the acquired EB subtype.
The results show that Ichthyosis and Neurofibromatosis were more frequently found in female
patients than male patients. Epidermolysis Bullosa and Tuberous Sclerosis Complex were more
frequently found in male patients than in female patients.
The age ranges differ depending on the disease. The results show that Epidermolysis Bullosa and
Ichthyosis are more frequently found in children, this could be due to the fact that these diseases can
shorten a person’s life span. This has changed due to research and development in treatment for these
patients. There are no children with Tuberous sclerosis or neurofibromatosis. This is because although
both these diseases have genetic causes, the symptoms don’t manifest till adolescence or adulthood
so patients don’t know or notice any symptoms till adulthood.
There were more patients from urban areas than rural areas of the country. This is true for patients
diagnosed with Ichthyosis and Neurofibromatosis. Those diagnosed with Tuberous Sclerosis were
found more in rural areas than urban areas of the country.
The Clinical findings for EB results shows that nail damage and mucosal involvement are commonly
found in patients with EB. 20 of more out of the 30 patients presented with these two complications.
Microstomia and Oesophagial stenosis are the least frequent complications seen in patients presenting
with EB in this clinic. The BEBS and DLQI scoring systems shows that majority of the patients have
low scores in both clinical assessment tests. This shows that majority of the EB patients have mild to
moderate clinical symptoms with a low impact on their quality of life.
Paraclinical investigations for Ichthyosis show that one in three patients presenting with Ichthyosis
had elevated IgE levels which could be because Ichthyosis has an association with Atopy and also
presents with elevated serum cholesterol. One in nine patients presents with increased WBC count.
Lab changes in patients with Ichthyosis are quite low. This shows us that most of the manifestations
for Icthyosis are cutaneous rather than systemic in a lot of these patients.

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10. Conclusion
During my time in Dermatology clinic at Colentina Hospital. I discovered five rare dermatological
diseases admitted into tertiary care from 2000-2018. These are Epidermolysis Bullosa, Ichthyosis,
Netherton’s syndrome, Neurofibromatosis and Tuberous Sclerosis.
The goal of this project is to visually present the distributions and incidence rates of the rare
dermatological diseases mentioned in this project. Epidermolysis Bullosa has the highest incidence
in the clinic and Tuberous Sclerosis has the lowest incidence of the five diseases.
The results show that Ichthyosis and Neurofibromatosis were more frequently found in female
patients than male patients. Epidermolysis Bullosa and Tuberous Sclerosis Complex were more
frequently found in male patients than in female patients.
The age ranges differ depending on the disease. The results show that Epidermolysis Bullosa and
Ichthyosis are more frequently found in children. There are no children with Tuberous sclerosis or
neurofibromatosis.
There were more patients from urban areas than rural areas of the country. This is true for patients
diagnosed with Ichthyosis and Neurofibromatosis. Those diagnosed with Tuberous Sclerosis were
found more in rural areas than urban areas of the country.
There is no cure for any of the five diseases mentioned. However the goal of the treatment given to
these patients is to alleviate the symptoms and give them the best lives possible. There is a lot of
research going into treatment to improve the lives of those with rare dermatological diseases such as
skin grafts to treat EB and Sicrolimus drug to treat Tuberous Sclerosis.

Commented TA2: I feel like I have writtenmy conclusion in the discussion. So what can I write here?

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