Genodermatoses - metabolic and ichthyoses

Question 1

Darier Disease autosomal dominant

Answer 1

True

Question 2

Darier Disease gene mutation?

Answer 2

Autosomal dominant missense mutation in ATP2A2

- mutation in calcium signalling , ATP2A2 encodes an endoplasmic reticulum (ER) Ca2+ ATPase pump, SERCA2

Question 3

What is the typical age of onset of Darier disease

Answer 3

6-20y, adolescence. Peak onset puberty 11-15y

Question 4

Darier Disease papules are limited to perifollicular location

Answer 4

False

Question 5

Darier disease can develop sterile vesicles and bullae

Answer 5

True

Question 6

Oral manifestations of darier disease

Answer 6

Cobblestone mucosa
Painless whitish papules or rugose plaques in 15-50%
Hard palate most common site of involvement, followed by gingiva, buccal mucosa and tongue

Question 7

Darier disease is associated with increased malignancy

Answer 7

True - rarely related to oncogenes types of HPV or changes in keratinocytes adhesion/proliferation. SCC of skin and upper GIT in mouse models

Question 8

List less common presentations of darier disease

Answer 8

Guttate hypopigmentation
Vesiculobullous lesions
Acral haemorrhagic lesions
Keratoderma (spiked)
Comedones, facial cysts, acne, conglobata
Periocular nodulocystic lesions
Alopecia, cutis verticis gyrata

Question 9

Gluteal cleft is frequently involved in darier disease

Answer 9

False - uncommonly although other intergtriginous sites are involved

Question 10

Extracutaneous manifestations of darier disease

Answer 10

Ocular - corneal ulcerations and staph end-ophthalmitis
Salivary gland obstruction
Infections - bacteria, viral, yeast, fungal
Neuro - epilepsy, intellectual impairment, and mood disorders have been reported in association with darier disease

Question 11

Histopathology of darier disease

Answer 11

Acantholysis due to disturbance in cell adhesion leading to suprabasilar cleft formation
- two types of dyskeratotic cells : corp ronds (acantholytic enlarged keratinocytes with partially fragmentednuclei surrounded by clear cytoplasm encircled by bright ring of collapsed keratin bundles)
& grains (shrunken parakeratotic nuclear remnants)

Question 12

Clinical subtypes of darier disease

Answer 12

1. Acral haemorrhagic type
2. Segmental types 1 and 2
   —> two types with distribution along lines of Blaschko
   —> more common is type 1 mosaicism (post zygotic. If have mutant cells in gonads, pt can have offspring with generalised darier). Type 2 segmental May have generalised Diarer with linear streaks of incr severity.

Question 13

Hailey hailey genetic mutation

Answer 13

ATP2C1 —> autosomal dominant

Question 14

Usual time of onset of Hailey Hailey disease

Answer 14

2nd or 3rd decade

Question 15

Nail features of hailey hailey

Answer 15

Longitudinal leukonychia

Question 16

Oral manifestations of hailey hailey

Answer 16

Painless oral EROSIONS , buccal, and also vaginal or conjunctival involvement

Question 17

Histology of hailey hailey

Answer 17

Loss of intercellular adhesions , larger areas of dyscohesion with single or groups of acantholytic cells are seen which have been likened to a delapidated brick wall
- dermal papillae are lined by single layer of basal cells and protrude into blister cavities —> “villi”

Question 18

Clinical subtypes of hailey hailey

Answer 18

Segmental type 1 —> caused by heterozygous post zygotic mutation in otherwise normal embryo , resulting in mosaic distribution of disease with age of onset and severity similar to non mosaic phenotype
Segmental type 2 —> earlier age of onset caused by post zygotic mutation also leading to a more severe disease in mosaic pattern

Question 19

FABRY disease mutation

Answer 19

X-linked lysosomal storage disorder

Due to defect in GLA (encodes a-galactosidase A)

Question 20

FABRY disease features

Answer 20

F - funny feelings (acral pain - painful crises -and paraesthesia), coarse Facies
A - angiokeratomas, abdo pain
B - breathing difficulties, cough and dyspnoea
R - renal impairment , retinal vascular abnormalities, corneal opacities
Y - hypohYdrosis, developmental delaY

Question 21

Facial features of FABRY

Answer 21

Periorbital fullness, bushy eyebrows, buccal and conjunctival teles, thick lips, prognathism , prominent earlobes

Question 22

Fucosidosis is associated with multiple angiokeratomas of skin and oral mucosa

Answer 22

True

Question 23

Fucosidosis differs from FABRY in which regard?

Answer 23

Fucosidosis exhibits neuro developmental delay, sinopulmonary infections, organomegaly and incr sweat chloride test

Question 24

Features of hypohidrotic ectodermal dysplasia

Answer 24

Sparse of absent hair
Missing or peg or conical teeth
Decreased sweat capacity 
Hypothermia can be fatal in first few years of life
Periorbital wrinkling or darkening
Raspy or hoarse voice 
Sebaceous hyperplasia on the face clinically resembles milia
Nails usually NORMAL

Question 25

T/F nails in hypohidrotic ectodermal dysplasia are usually normal

Answer 25

True

Question 26

Features of Clouston syndrome

Answer 26

Autosomal dominant GJB6 Wiry, brittle and pale hair Hair and nails with normal teeth and sweating but nails gradually thicken throughout childhood Adults - nail plate grows slowly, thickened and separate from nail bed distally Oral leukoplakia described Sparse eyelashes can predipose pt to conjunctivitis and blepharitis Patchy alopecia is common

Question 27

How is EHK inherited?

Answer 27

Autosomal dominant with 50% spontaneous mutations in KRT1 and 10

Question 28

EHK presentation

Answer 28

Newborn - can have widespread bullae, erythroderma, denuded skin, secondary sepsis, electrolyte imbalance +/- focal areas of hyperkeratosis Later infancy to adulthood - localised to generalised hyperkeratosis with rare, focal bullae secondary to infection - see dark, warty scales with spiny ridges more so in the flexures ==> widespread corrugated patterned scale with isolated bullae

Question 29

EHK histology

Answer 29

EHK with coarse ireregular hypergranulosis and increased keratohyalin granules + parakeratosis often in association with Disrupted cell membranes

Question 30

EHK widespread blistering clears after newborn period

Answer 30

True

Question 31

Lamellar ichthyosis is autosomal recessive

Answer 31

True

Question 32

Lamellar ichthyosis due to which gene?

Answer 32

Transglutaminase-1

Question 33

Features of lamellar ichthyosis

Answer 33

Newborn: collodion baby with translucent membrane encasing body, ectropion, eclabium, generalised erythroderma Adult/child: generalised , dark plate like scale that is increased in the flexures. Can have erythroderma and ectropion, PPK, Hypohidrosis

Question 34

Non bullous CIE aka CIE , presents with collodion membrane

Answer 34

True

Question 35

Harlequin foetus gene mutation

Answer 35

ABCA12 - encodes protein transporting epidermal lipids

Question 36

Sjogren Larsson Syndrome triad

Answer 36

Congenital ichthyosis Gradual development of Di or tetraplegia Mental retardation

Question 37

Sjogren larsson inheritance

Answer 37

FALDH (fatty aldehyde dehydrogenase) | Autosomal recessive

Question 38

Ectropion and collodion membrane are common features of Sjogren Larsson

Answer 38

False, rare

Question 39

What is the pathognomonic ocular finding in Sjogren Larsson

Answer 39

Perifoveal glistening white dots - in ocular fundus - represents a form of juvenile macular degeneration

Question 40

Clinical features of Sjogren Larsson

Answer 40

``` Scissor gait Delayed motor development Seizures in 40% Dental/osseous dysplasia Hypertelorism Pruritus ```

Question 41

Sjogren Larsson not pruritic

Answer 41

False, persistent pruritus which contrasts to other ichthyosis

Question 42

Refsum syndrome inheritance

Answer 42

PAHX gene affecting catalysation of phytanic acid | Autosomal recessive

Question 43

Features of Refsum syndrome

Answer 43

Retinitis pigmentosum - with salt and pepper dyspigmentation , night blindness - sensorineural deafness - cardiac arrhythmia and heart block - MSK wasting - skin only mild ichthyosis

Question 44

Conradi-Hunermann-Happle syndrome inheritance

Answer 44

Emopamil binding protein EBP | X linked dominant

Question 45

Conradi-Hunermann-Happle syndrome clinical features

Answer 45

icthyosiform erythroderma in Blaschko’s lines in infancy - resolving with follicular atrophoderma or hyperpigmentation - coarse patchy alopecia - Stippled epiphyses (calcification punctate) - facies: frontal bossing, macrocephaly, flat nasal root

Question 46

Features of CHILD syndrome

Answer 46

NSDHL X linked dominant (no sons only daughter have life) Congenital hemidysplasia with icthyosiform erythroderma and limb defects Ipsilateral alopecia Severe nail dystrophy Can have stippled epiphyses like CHHunermann

Question 47

Neutral lipid storage disease inheritance and features

Answer 47

ABHD5 autosomal recessive - can have collodion membrane - cataracts, sensorineural deafness, developmental delay are frequent features Growth retardation, ataxia, microcephaly and renal insufficiency

Question 48

Neutral lipid storage disease is characterised by which granulocytes anomaly

Answer 48

Jordan’s anomaly — lipid containing vacuoles in granulocytes and monocytes but NOT lymphocytes or erythrocytes

Question 49

Netherton syndrome hair abnormalities

Answer 49

Trichorrhexis invaginata (bamboo hair) , trichorrhexis nodosa, helical hair, pili torti

Question 50

Netherton syndrome gene

Answer 50

SPINK5 causing lack of functional LEKTI | Collodion baby possible but NOT generally a feature

Question 51

Netherton syndrome experience immunodeficiency

Answer 51

True involving memory B and NK cells

Question 52

How is trichothiodystrophy inherited?

Answer 52

Autosomal recessive - [possible cases of X-linked transmission]

Question 53

What is trichothiodystrophy

Answer 53

Group of heterogeneous neuroectodermal disorders —> associated with photosensitivity, reduced stability or altered function of general transcription factor (TFIIH) PIBIDS: photosensitivity, ichthyosis, brittle hair, infertility, developmental delay, short stature Obligatory finding in all types is short, unruly , fragile scalp/eyebrow/eyelash hair due to abnormally low Sulfur content ie. deficient cysteine or methionine Nail changes: Thinning, longitudinal ridging, yellow discolouration, splitting, onychogryphosis

Question 54

What are extracutaneous manifestations of Trichothiodystrophy

Answer 54

``` intellectual disability —> microcephalic —> ataxia —> spastic paralysis —> brain MRI may show dysmyelination, cerebellar atrophy, dilated ventricles ```

Question 55

How to investigate trichothiodystrophy?

Answer 55

Light microscopy of hair shaft demonstrates transverse fractures (trichoschisis) in conjunction with irregular surface and diameter Occasionally a nodal appearance similar to trichorrhexis nodosa or 180 degree twists as in pili torti may be observed Polarising light microscopy is gold standard to detect “tiger tail” bands If ichthyosis is present, histopathology similar to ichthyosis vulgaris can be seen - Molecular testing Hair Sulfur content can be semi quantitatively analysed by scanning electron microscopy

Question 56

How is Erythrokeratoderma Variabilis | Inherited?

Answer 56

Rare disorder predominantly autosomal dominant Nearly complete penetrate but considerable intra and interfamilial variability Mutations in GJB3, GJB4 and occasionally GJA1 Genes encode gap junctions connexin 31, connexin 30.3 and connexin 43

Question 57

Individual lesions of Erythrokeratoderma Variabilis | Last for days to weeks

Answer 57

False mins to hours

Question 58

Progressive symmetric erythrokeratoderma - inheritance - presentation

Answer 58

Can have GJB4 mutations like EKV more recently, los of function mutations in KRT83 have been found ASSESSMENT: usually begins during infancy or early childhood with development of fixed, sharply demarcated or polycyclic hyperkeratotic plaques on an erythematous base covered by fine scale with a rough verrucous surface - especially over JOINTS Symmetric distribution on extremities, buttocks and face Especially on cheeks diffuse erythematous PPK occurs in at least half

Question 59

What does KID syndrome stand for

Answer 59

keratitis, ichthyosis, deafness

Question 60

Inheritance of kid syndrome

Answer 60

most harbour mutations in GJB2 Encodes connexin 26 Autosomal dominant manner but >90% reported cases have been sporadic

Question 61

Clinical features of KID syndrome

Answer 61

Considerable variability in cutaneous features First manifestation often transient erythroderma at birth or during infancy Later most patients develop symmetrical, well demarcated, hyperkeratotic plaques with erythematous base and rough, ridged or verrucous surface (ie. erythrokeratoderma) —> these favour extensor knees, elbows and face often with radial furrows around mouth Nails can be dystrophic and show leukonychia Hair - most have normal hair, some with alopecia of scalp/lash/brows or have lustreless hair Other cutaneous manifestations: - follicular occlusion triad, cysts, proliferating trichilemmal cyst, rare reports of malignant lesions