Genodermatoses - metabolic and ichthyoses Flashcards
Darier Disease autosomal dominant
True
Darier Disease gene mutation?
Autosomal dominant missense mutation in ATP2A2
- mutation in calcium signalling , ATP2A2 encodes an endoplasmic reticulum (ER) Ca2+ ATPase pump, SERCA2
What is the typical age of onset of Darier disease
6-20y, adolescence. Peak onset puberty 11-15y
Darier Disease papules are limited to perifollicular location
False
Darier disease can develop sterile vesicles and bullae
True
Oral manifestations of darier disease
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
Darier disease is associated with increased malignancy
True - rarely related to oncogenes types of HPV or changes in keratinocytes adhesion/proliferation. SCC of skin and upper GIT in mouse models
List less common presentations of darier disease
Guttate hypopigmentation Vesiculobullous lesions Acral haemorrhagic lesions Keratoderma (spiked) Comedones, facial cysts, acne, conglobata Periocular nodulocystic lesions Alopecia, cutis verticis gyrata
Gluteal cleft is frequently involved in darier disease
False - uncommonly although other intergtriginous sites are involved
Extracutaneous manifestations of darier disease
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
Histopathology of darier disease
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)
Clinical subtypes of darier disease
- Acral haemorrhagic type
- 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.
Hailey hailey genetic mutation
ATP2C1 —> autosomal dominant
Usual time of onset of Hailey Hailey disease
2nd or 3rd decade
Nail features of hailey hailey
Longitudinal leukonychia
Oral manifestations of hailey hailey
Painless oral EROSIONS , buccal, and also vaginal or conjunctival involvement
Histology of hailey hailey
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”
Clinical subtypes of hailey hailey
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
FABRY disease mutation
X-linked lysosomal storage disorder
Due to defect in GLA (encodes a-galactosidase A)
FABRY disease features
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
Facial features of FABRY
Periorbital fullness, bushy eyebrows, buccal and conjunctival teles, thick lips, prognathism , prominent earlobes
Fucosidosis is associated with multiple angiokeratomas of skin and oral mucosa
True
Fucosidosis differs from FABRY in which regard?
Fucosidosis exhibits neuro developmental delay, sinopulmonary infections, organomegaly and incr sweat chloride test
Features of hypohidrotic ectodermal dysplasia
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
T/F nails in hypohidrotic ectodermal dysplasia are usually normal
True
Features of Clouston syndrome
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
How is EHK inherited?
Autosomal dominant with 50% spontaneous mutations in KRT1 and 10
EHK presentation
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
EHK histology
EHK with coarse ireregular hypergranulosis and increased keratohyalin granules + parakeratosis often in association with Disrupted cell membranes
EHK widespread blistering clears after newborn period
True
Lamellar ichthyosis is autosomal recessive
True
Lamellar ichthyosis due to which gene?
Transglutaminase-1
Features of lamellar ichthyosis
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
Non bullous CIE aka CIE , presents with collodion membrane
True
Harlequin foetus gene mutation
ABCA12 - encodes protein transporting epidermal lipids
Sjogren Larsson Syndrome triad
Congenital ichthyosis
Gradual development of Di or tetraplegia
Mental retardation
Sjogren larsson inheritance
FALDH (fatty aldehyde dehydrogenase)
Autosomal recessive
Ectropion and collodion membrane are common features of Sjogren Larsson
False, rare
What is the pathognomonic ocular finding in Sjogren Larsson
Perifoveal glistening white dots
- in ocular fundus
- represents a form of juvenile macular degeneration
Clinical features of Sjogren Larsson
Scissor gait Delayed motor development Seizures in 40% Dental/osseous dysplasia Hypertelorism Pruritus
Sjogren Larsson not pruritic
False, persistent pruritus which contrasts to other ichthyosis
Refsum syndrome inheritance
PAHX gene affecting catalysation of phytanic acid
Autosomal recessive
Features of Refsum syndrome
Retinitis pigmentosum - with salt and pepper dyspigmentation , night blindness
- sensorineural deafness
- cardiac arrhythmia and heart block
- MSK wasting
- skin only mild ichthyosis
Conradi-Hunermann-Happle syndrome inheritance
Emopamil binding protein EBP
X linked dominant
Conradi-Hunermann-Happle syndrome clinical features
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
Features of CHILD syndrome
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
Neutral lipid storage disease inheritance and features
ABHD5 autosomal recessive
- can have collodion membrane
- cataracts, sensorineural deafness, developmental delay are frequent features
Growth retardation, ataxia, microcephaly and renal insufficiency
Neutral lipid storage disease is characterised by which granulocytes anomaly
Jordan’s anomaly — lipid containing vacuoles in granulocytes and monocytes but NOT lymphocytes or erythrocytes
Netherton syndrome hair abnormalities
Trichorrhexis invaginata (bamboo hair) , trichorrhexis nodosa, helical hair, pili torti
Netherton syndrome gene
SPINK5 causing lack of functional LEKTI
Collodion baby possible but NOT generally a feature
Netherton syndrome experience immunodeficiency
True involving memory B and NK cells
How is trichothiodystrophy inherited?
Autosomal recessive - [possible cases of X-linked transmission]
What is trichothiodystrophy
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
What are extracutaneous manifestations of Trichothiodystrophy
intellectual disability —> microcephalic —> ataxia —> spastic paralysis —> brain MRI may show dysmyelination, cerebellar atrophy, dilated ventricles
How to investigate trichothiodystrophy?
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
How is Erythrokeratoderma Variabilis
Inherited?
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
Individual lesions of Erythrokeratoderma Variabilis
Last for days to weeks
False mins to hours
Progressive symmetric erythrokeratoderma
- inheritance
- presentation
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
What does KID syndrome stand for
keratitis, ichthyosis, deafness
Inheritance of kid syndrome
most harbour mutations in GJB2
Encodes connexin 26
Autosomal dominant manner but >90% reported cases have been sporadic
Clinical features of KID syndrome
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
