Genoderms Flashcards
1
Q
Peutz Jehger genetics
A
germ line mutations in the Serine Threonine Kinase tumor-suppressor gene found on chromosome 19p13.3 (also called STK11/LKB1).
Autosomal dominant
30% sporadic
2
Q
XP genes
A
7 types of genes XP A - G
3
Q
Life expectancy of XP
A
50s-60s
4
Q
Ichthyosis vulgaris Epidemiology
A
- 1/100 - 1/200
- semi-autosomal dominant
- FLG mutation
- can be heterozygous (mild-mod) or homozygous (severe)
- more common in Caucasians
5
Q
Ichthyosis vulgaris Clinical
A
- Heterozygous
- not clinically apparent at birth
- in infant/toddler years develop scale to extensor surfaces
- as get older, develop larger scale with adherent centres and turning out scale on this
- hyperlinear palms
- Homozygous
- 2 alleles affected
- erythematous and scaling at birth
- more severe
- scaling to forehead, cheeks, arms and legs, trunk
- Associated with atopy - allergic rhinitis, asthma and eczema
6
Q
Ichthyosis vulgaris Histology
A
- orthokeratosis and hyperkeratosis
- absence of granular layer
- on electron microscopy there are no keratin hyaline granules or granular layer in ~ 50% cases
7
Q
Ichthyosis vulgaris Treatment
A
- keratolytics
- emollients
- humectants
8
Q
Ichthyosis vulgaris pathogenesis
A
- Profillagrin assists in squamous cell compaction
- It turns into filagrin, which then gets broken down to amino acids (particularly histidine) as a natural moisturiser
- Loss of this results in:
- increased cornification
- transepidermal water loss
- increased atopy
9
Q
Steroid Sulfatase Deficiency epidemiology
A
- 1/2000 - 1/9000
- X linked recessive disorder
- Asymptomatic female carriers
- Exclusively in males
10
Q
Steroid Sulfatase Deficiency pathogenesis
A
- Deletion of STS gene on chromosome Xp22.31
- impaired steroid sulfatase results in impaired hydrolysis of cholesterol + DHEAS resulting in cholesterol accumulation in the epidermis
- elevated cholesterol can also inhibit transglutaminase-1
11
Q
Steroid Sulfatase Deficiency clinical
A
- Birth: lack of progression/ requires caesarean due to reduced oestrogen
- Neonate: mild erythema, generalised peeling, large translucent scale
- Childhood: dirty neck, lower legs, pre-auricular, typical polyglonal, dark-brown adherent scales
- Other:
- Corneal opacities in 10-50%
- Green colour blindness
- Cryptorchidism, testicular cancer, hypogonadism, ADHD
- Also can be associted with larger, contiguous deletion like Kallman’s
12
Q
Epidermolytic Ichthyosis epidemiology
A
- 1/200 000 - 250 000
- Autosomal dominant with complete penetrance
- M=F
- 50% new spontaneous mutation
13
Q
Epidermolytic Ichthyosis pathogenesis
A
- Defect in KRT1 or KRT10
- KRT1 induces palmoplantar
- Results in bad keratin alignment and filament assembly –> compromises strength and cellular integrity of the epidermis, resulting in cytolysis, acanthosis, hyperkeratosis from hyperproliferation and reduced desquamation resulting in clumping of keratin
- this results in increased TEWL and bacterial infections
14
Q
Epidermolytic Ichthyosis clinical
A
- think ‘stinky’ and keratinocyte fragility disease
- Neonate: erythroderma, peeling, erosions, blistering, fragility - incr risk of sepsis and fluid loss
- As they get older: hyperkeratosis, blistering fades
- Flexures: ridges along the skin line
- Extensors: cobblestoning
- Palmoplantar keratoderma –> results in contractures
- Complications: infections, body odour, reduced QoL, hair loss
- Variant: epidermolytic epidermal naevi
- this is a post zygotic mutation with porcupine like streaks
- if gonadal, can pass on
- Prognosis: improves possibly after puberty - goes from generalised to localized
15
Q
Epidermolytic Ichthyosis histology
A
- Epidermolytic hyperkeratosis, orthokeratosis, acanthosis, hypergranular layer, cytolysis of the suprabasal and granular layers –> results in an intraepidermal blister
- Keratinocyte vacuolization, dense clumps of keratin intermediate filaments
- Lymphocytic peri-vascular infiltrate
- Can diagnosis prenatally: foetal skin biopsy
16
Q
Epidermolytic Ichthyosis treatment
A
- Neonate: ICU, fluids, antibiotics, padding, lubricants –> can heal quickly
- Older:
- Keratolytics - urea, SA, alpha hydroxy (stings)
- Tretinoin + vitamin D –> stings
- Emollients and humectants
- Mechanical abrasion
- Anti-septics
- Antibiotics
- Systemic retinoid - improves the hyperkeratosis but worsens the fragility
17
Q
Superficial epidermolytic ichthyosis
A
- this is not a big deal
- rare autosomal dominant ichthyosis
- heterozygous mutations in KRT2 - this is in the upper most spinous and granular cell
- they just get trauma induced blisters, then hyperkeratosis develops over joints, flexures, dorsa of hands and feet
- Histo: orthokeratosis hyperkeratosis, acanthosis, granular cell layer vacuolization, occasionally results in intraepidermal separation
- Ddx: EBS
- Treatment same as EI
18
Q
Superficial epidermolytic ichthyosis
A
- this is not a big deal
- rare autosomal dominant ichthyosis
- heterozygous mutations in KRT2 - this is in the upper most spinous and granular cell
- they just get trauma induced blisters, then hyperkeratosis develops over joints, flexures, dorsa of hands and feet
- Histo: orthokeratosis hyperkeratosis, acanthosis, granular cell layer vacuolization, occasionally results in intraepidermal separation
- Ddx: EBS
- Treatment same as EI
19
Q
Colloidon Baby Causes
A
- Causes - SLAUGHT CENN
- Sjogren Larrson
- Lamellar ichthyosis
- Gaucher disease
- Hay-Well syndrome
- Trichothiodystrophy
- Congenital ichthyosiform erythroderma
- Netherton’s
- Neutral lipid storage disease
- 10% have milder ‘self-healing’ phenotype
- dynamic phenotype dependant on environment
- fully inactive encoded protein in utero but not after birth
20
Q
Colloidon Baby Clinical
A
- Birth: premi, increased morbidity and mortality
- Neonat:
- taut, shiny transparent membrane like ‘plastic wrap’
- thickened
- tautness results in ectropion, eclabium, hypoplasia of nasal and auricular cartilage
- sucking impairment –> malnutrition, dehydration
- pulmonary ventilation impairment –> pneumonia
- Then membrane dries and cracks up
- Fissures –> TEWL, infection –> sepsis
- Circular bands of skin –> vascular constriction
- 2-4 weeks –> peels off in sheets and becomes underlying phenotype
21
Q
Colloidon baby histology
A
- Thick, orthokeratotis SC
- don’t bother doing a biopsy - wait until resolved
- can do immunostain for transglut-1 in upper fermis
- can do multigene molecular testing
22
Q
Colloidon baby treatment
A
- controlled environment
- fluid and electrolyte monitoring
- humidified incubator –> wet compresses, light emollients
- don’t mannually remove membrane, it just increases risk of infection
23
Q
Colloidon baby treatment
A
- controlled environment
- fluid and electrolyte monitoring
- humidified incubator –> wet compresses, light emollients
- don’t mannually remove membrane, it just increases risk of infection
24
Q
Lamellar ichthyosis epi, genetics, path
A
Epidemiology and genetics
- 1 in 200 000 - 300 000
- autosomal recessive in transglutaminase 1 - TGM1
Pre-natal diagnosis:
- CVS/amniocentesis: TGM1 gene mutation, or foetal skin biopsy at 22 weeks
Path
- TGM1 interferes with normal cross linking of structural proteins –> defective cornification and desquamation
25
Q
Lamellar ichthyosis clinical
A
- Neonate: colloidon baby –> translucent membrane, ectropion, eclabium, erythroderma, risk of sepsis
- Child: large, dark, plate like scale, increased in flexures, erythroderma, ectropion, hypohidrosis
- Hair: scarring alopecia
- Nails: secondary dystrophy
26
Q
Lamellar ichthyosis diagnosis and management
A
Dx: - Transglutaminase-1 expressor Management: - Neonate --> NICU, high humidity chamber, emollient - Later: retinoid/emollient
27
Q
Netherton epidemiology
A
- Autosomal recessive
- 1 in 50 000
28
Q
Netherton pathogenesis
A
- SPINK5 mutation –> more than 70 SPINK5 mutations
- Encodes the multi-domain serine protease inhibitor LEKTI, which is in the lamellar granules of the epitheliala any lymphoid tissue
- This results in increased serine protease activity –> disturbs the proper formation of the lamellar lipid bilayer system in the stratum corneum
- Hastened degradation of desmoglein 1 –> disintegration and shedding of horny cells –> superficial clefts, and disrupted skin barrier
- Also results in loss of anti-inflammatory and anti-microbial mechanisms
- Hair: decreased cross-linkage of hair keratin structures
29
Q
Netherton clinical
A
- Cutaneous
- Neonate: erythroderma (similar to CIE) and continuous peeling of skin. At risk of electrolyte imbalances, failure to thrive, pneumonia, sepsis.
- Gradually evolves into serpiginous or circinate scaling and erythematous plaques –> ichthyosis linearis circumflexa which are double-edged scale, trunk and extremities, pruritic
- eczematous plaques in flexures
- scalp can have thick scale
- Hair shaft abnormalities
- Usually improves with age
- Trichorrhexis invaginata is bamboo hair –> ball and socket appearance
- Can also have pili torti (flat and twisted), trichorrhexis nodosa (weak spots that causes it to break), helical hair
- Immune dysregulation
- Atopy, and immunodeficiency involving memory B cells and natural killer cells
- High IgE
- Eosinophilia and allergy to foods and other antigens is common –> urticaria, angioedema
- Increased IL-17
- Recurrent lung and skin infections
- Increase in SCCs and BCCs in 30s
- Extra:
- Failure to thrive when a child due to enteropathy with villus atrophy
30
Q
Netherton pathology
A
- Parakeratotic hyperkeratosis, with diminished or absent granular layer
- Acanthosis, papillomatosis
- often dense, almost band like lymphohistioyctic perivascular infiltration in the papillary dermis
- Subcorneal clefting, spongiosis, exocytosis
- Eosinophilic
- Hair: ball and socket, or match stick and golf tee
- Ultrastructural abnormalities in epidermal lipid system –> premature secretion of lamellar body contents in the upper dermis as well as the presence of intercellular electron dense accumulations and abnormal splitting in the superficial stratum corneum
31
Q
Netherton - genteic test and immunostain
A
- SPINK5 –> can be prenatal in CVS or amniocentesis
- Immunostain: anti-LEKTI antibodies
32
Q
Netherton ddx
A
- CIE
- Erythrodermic psoriasis
- Primary immunodeficiencies - Wiskott Aldrich, Omenn, IPEX
- AD-hyper IgE syndrome –> high IgE, eczema, neonatal papulopustular eruption
- Acrodermatitis enteropathica
- Peeling skin syndromes
33
Q
Netherton treatment
A
- Symptomatic
- Emollients, keratolytics, tretinoin, calcipotrial, steroids
- Topical tacrolimus –> however they have increased absorption of this and it can go systemic, elidel has been more successful
- Anti-microbial obviously
- IVIG: fewer infections, reduced skin inflammation, growth and weight gain
- Pruritis - oral anti-histamines
- Systemic retinoids –> exacerbates some, improves others
- Phototherapy
- Watch this space: IL-17
34
Q
Darier epi
A
- 1/100 000 to 1/30 000
- M=F
- Autosomal dominant with complete penetrance
35
Q
Darier pathogenesis
A
- ATP2A2 gene which encodes SERCA (calcium pump) –> chronically low calcium stores within the endoplasmic reticulum –> acantholysis and apoptosis
- More than 240 pathogenic mutations of ATP2A2 have been identified
36
Q
Darier cutaneous features
A
- 70% of patients begins between 6 and 20 years, peak onset during puberty
- Keratotic, crusted red-brown papular rash in seborrheic distribution involving the trunk, scalp, face and lateral aspects of the neck
- Pruritic
- Lesions become confluent and may form papillomatous masses
- Small 2-3 mm hypomelanotic macules may be admixed with keratotic papule and occasionally are a predominant feature
- Rarely - sterile vesicles and bullae
- Can get intertriginous ++ as well, malodor
- 50%: 2-4 mm skin coloured or brownish, flat-topped papules similar to flat warts on the dorsal aspects of the hands and feet
- Nails: longitudinal red and/or white lines, longitudinal ridging and fissuring, wedge-shaped subungual hyperkeratosis, brittle, break easily and form V-shaped notches
- Mouth: whitish papule or rugose plaques in 15-50% –> hard palate
37
Q
Darier’s extracutaneous
A
- Salivary glands: painful swelling
- Neuropsychiatric: epilepsy, intellectual impairment, mood disorders, bipolar, schizophrenia –> not fully established
- Ocular: corneal ulcerations
38
Q
Darier’s complications
A
- secondary infections: Staph, HPV, HSV
- If sudden onset and rapid spread of vesicular and crusted lesions with fever and malaise –> high index of suspicion for Kaposi varicelliform
- SCC
39
Q
Darier’s clinical subtypes
A
- Acral haemorrhagic type
- sharply demarcated, red to blue-black macules on the palms and soles as well as the dorsal aspects of the hands
- Segmental types 1 and 2
- Type 1 mosaicism - post zygotic mutation in ATP2A2 during embryogenesis. If mutant cells in the gonads –> offspring has generalised Darier
- Type 2 mosaicism - generalised plus linear streaks - have heterozygous germline mutation and then also get a post zygotic hit
40
Q
Darier’s exacerbating factors
A
- UV exposure
- Sweating, heat, occlusion
- Medications: lithium
41
Q
Darier’s histo
A
- Acantholysis –> corresponds to a loss of desmosomes and detachment of keratin filaments
- Dyskeratosis –> characterized by nuclear condensation and perinuclear keratin clumping
- Corps ronds - acantholytic enlarged keratinocytes in the malphigian layer with darkly staining and partially fragmented nuclei
- Grains - small, oval cells in the stratum corneum - intensely eosinophilic cytoplasm composed of collapsed keratin bundles containing shrunken parakeratotic nuclear remnants. Likely derived from corps ronds
- Epidermis: papillomatosis and hyperkeratosis
- Ddx: Grover disease (tends to be more acantholysis and less dyskeratosis)
42
Q
Darier’s ddx
A
- Accrokeratosis verruciformis of Hopf (closely linked, sometimes have this then develop Darier, ATP2A2 gene associated as well)
- Severe seb derm
- Grover’s
- Flexural: pemphigus vegetans, pemphigoid vegetans, blastomycosis like pyoderma
43
Q
Darier’s rx
A
- GSCM: lightweight clothes, sun protection, sweat minimisation, reduction to UV exposure, antimicrobial cleansers
- Topicl:
- Retinoids as monotherapy, although irritates
- Antibiotics and antifungals
- Calcineurin inhibitors
- 5-FU
- COX-2 inhibition
- Systemic
- Systemic retinoids - significant improvement in 90%. Use is limited by their side effects, relapse occurs after cessation of therapy, so only use for severe disease
- OCP may help with pre-menstrual exacerbations
- Cyclosporin
- Naloxone
- Surgical therpay
- Split-thickness grafting, dermabrasion, laser (CO2 or er yag)
44
Q
Diffuse palmoplantar keratoderma epi and path
A
Epidemiology
- Most common form of diffuse
- > 4.4 per 100 000 in Northern Island, 1 in 200 in Sweden
Pathogenesis
- Autosomal dominant, mutations in KRT1 and KRT9
- KRT9 is limited to the suprabasal cell layers of the palmar and plantar skin
- Mutations result in disruption to keratin filament assembly - resulting in tonofilament clumping and cytolysis that results in blistering and hyperkeratosis
- In the palmoplantar skin, KTN9 is thought ti partner with KRT1
45
Q
Diffuse palmoplantar keratoderma clinical
A
- Palmoplantar skin is initially red, followed by thick, yellow hyperkeratosis by 3-4 years of age
- Adults: smooth, waxy surface and sharply demarcated erythematous border sparing the dorsal aspects of the palms and soles
- Rarely get blistering and fissuring, but can occur if placed on retinoids
- Occasionally thickened knuckle pads and nails
- In ‘tonotubular’ EPPK (?just keratin 1) can be painful
- Greither type/Unna-Thorst - PPK transgrediens (extension to dorsum) and progrediens –> limited transgredient lesions over the Achilles tendon, elbows and knees
46
Q
Diffuse palmoplantar keratoderma histology
A
- Epidermolytic hyperkeratosis: vacuolated suprabasal keratinocytes with round or ovoid eosinophilic inclusions that represent large tonofilament aggregates
- ‘Tonotubular’ subtype: electron microscopy shows whorls of keratin containing tubular structures
- Also: coarse keratohyalin granules, acanthosis, marked orthohyperkeratosis
- With keratinocyte cytolysis, can get intraepidermal blistering and a mild superficial dermal inflammatory infiltrate
47
Q
Diffuse palmoplantar keratoderma management
A
- mechanical debridement with a blade or dental drill is useful for troublesom areas - then apply a keratolytic
- Options for keratolytics: 50% propylene glycol in water under plastic occlusion, lactic acid and urea-containing creams and lotions, salicylic acid 4-6% petrolatum but be careful in children as can result in systemic absorption
- Systemic retinoids: improve hyperkeratosis but can result in peeling
- Genoderm textbook suggests: saltwater soaks (3% NaCl for 30 minutes), followed by 40% urea under occlusion overnight to reduce hyperkeratosis, paring with a sharp knife is acceptable but avoid rubbing
48
Q
Hailey hailey epi
A
- No data on prevalence
- Autosomal dominant with complete penetrance
- Age of onset varies a lot though
- Particular mutations may be associated with primarily genitoperineal involvement
49
Q
Hailey hailey path
A
- ATP2C1 gene, which encodes Ca ATPase hSPCA1 that is localized to the Golgi apparatus –> it transports calcium and magnesium, and sequesters calcium within the golgi lumen
- Likely haploinsufficiency, most mutations encode premature termination codons
- Impaired calcium sequestration results in acantholysis
50
Q
Hailey hailey clinical complications and subtypes
A
- Cutaneous
- Onset 2nd-3rd decade of life, can occur later
- Flexural: axillae, groin, lateral aspects of neck, perianal. Women: inframammary and vulval.
- Less commonly: scalp, antecubital, popliteal fossae, trunk
- Initially: flaccid vesicle, ruptures easily, often overlooked
- Then blisters –> macerated or crusted erosions, spreads peripherally producing a circinate border with crusts and small vesicles
- Chronic, moist macerated, malodorous vegetations and painful fissures
- Relapses and remits
- Doesn’t scar, but leaves PIH
- Mucosal involvement rarely
- ++ Odour and pruritus
- Nail: longitudinal leukonychia
- Clinical Subtypes
- Segmental 1: postzygotic mutation –> mosaic distribution
- Segmental 2: generalized then second hit postzygotic, resulting in segmental more pronounced. Affected areas have acantholysis within adnexal structures, so can’t ablate this one.
- Things that make it worse: friction, heat, sweat, staph infection
- Complications
- Infectious –> bacterial, fungal, viral. If recalcitrant swab for HSV. Rarely Kaposi varicelliform - fever, spreading vesicular eruption
- Malignant transformation –> SCC
