Genoderm Flashcards
1
Q
Trichothiodystrophy
o Inheritance
o Gene
Jain
A
o Inheritance – AR
o Gene – ERCC2 & ERCC3 (Cockayne Syndrome ERCC6 & 8)
2
Q
Trichothiodystrophy - Clinical Mnemonic
Jain
A
PIBIDS
• Photosensitivity (50%)
• Ichthyosis (variable)
• Brittle Hair (alternating bright/dark ‘tiger tail’, flattened hair shafts ‘ribbon’)
• Intellectual impairment
• Decreased Fertility
• Short stature, receding chin, protruding ears
NB TrichThiodystrophy -> TigerTail
3
Q
Ataxia–telangiectasia
- Inheritance
Jain
A
AR
4
Q
Ataxia–telangiectasia
- Gene
Jain
A
ATM mutation – cannot repair chromosal strand breaks (ionizing radiation sens)
5
Q
Ataxia Telangiectasia
- Principle change in cerebellum
Jain
A
Decr Purkinje Fibers
6
Q
Ataxia Telangiectasia
- Immunological changes
- Risk of which Cas?
Jain
A
Low IgA/E/G –> increased sinopulmonary infections
Incr Lymphoreticular Malignancy
Incr Breast Ca Risk
7
Q
Ataxia Telangiectasia
- Clinical presentation
Jain
A
- First symptom – ataxia (2-3yo)
- Telangiectasiae on bulbar conjunctivae – spread to cheeks and ears
- Premature aging (atrophic/sclerotic face)
- Recurrent sinopulmonary infections
8
Q
Basal Cell Naevus Syndrome
- Inheritance?
Jain
A
AD
9
Q
Basal Cell Naevus Syndrome
- Gene?
Jain
A
Gene – PTCH (Patched)
Inhibits Sonic Hedgehog signalling – PTCH inhibits Smoothened (SMO) signalling – when removed, activation of Gli and downstream targets
10
Q
Basal Cell Naevus Syndrome
- Clinical Features?
Jain
A
- Numerous BCCs
- Palmoplantar Pits
- Odontogenic cysts
- Facies (frontal bossing, hypertelorism)
- Cataracts
- Glaucoma
- Bifid Ribs
- Calcification of Falx Cerebrum
- Agenesis of the Corpus Callosum
- Ovarian Fibromas
- Medulloblastoma
- Meningioma
11
Q
NF1
- Inheritance
Jain
A
AD
12
Q
NF1
- Gene
Jain
A
NF-1 (encodes neurofibromin – tumour suppressor)
13
Q
NF1
- Diagnostic Criteria + other clinical manifestations
Jain
A
2+ of CAFE SPOT:
C: café-au-lait spots (6+ CALM or 2+ NF or 1 plexiform NF (CALM >0.5cm prepubertal, >1.5cm postpubertal))
A: axillary or inguinal freckling (crowe’s sign axillary)
F: fibromas (neurofibroma (two or more) or plexiform neurofibroma (one))
E: eye hamartomas (Lisch nodules)
S: skeletal abnormalities, e.g. sphenoid wing dysplasia, leg bowing/long bone cortex thinning
P: positive family history
OT: optic tumour (optic nerve glioma)
Other: HTN, Mental retardation, Seizures, kyphoscoliosis, endocrine disorder (precocious puberty, acromegaly, thyroid/parathyroid problems)
14
Q
NF1
- Risk of which malignancies?
Jain
A
Optic glioma, Malignant peripheral nerve sheath tumour, neurosarcoma, juvenile myelomonocytic leukaemia, rhabdomyosarcoma
15
Q
NF1
- What is Legius Syndrome in comparison
Jain
A
General
o NF-1-like syndrome
o SPRED-1 mutation (suppression RAS/MAP kinase)
Clinical
o Similar to NF1 though no tumour growth – no lisch nodules, NFs, CNS tumours
16
Q
Carney Complex
- aka?
- Inheritance/Gene
Jain
A
o Aka NAME or LAMB Syndrome
o Inheritance – AD
o Gene – PRKAR1A
17
Q
Carney Complex
- Clinical Features?
Jain
A
o Multiple ephelides, blue naevi, lentigines (centrofacial/mucosal)
o Cutaneous myxomas (flesh-coloured papules over the ears, eyelids, nipples)
o Cardiac myxomas – can cause CHF, pulmonary oedema/embolism
o Primary pigmented nodular adrenocortical disease (produces Cushings)
o Risk of various tumours (separate card)
NAME (Naevi, atrial myxoma, myxoid tumours, ephilides)
LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, blue naevi)
18
Q
Carney complex
- tumour risk?
Jain
A
o Testicular tumours
o Pituitary GH-secreting tumours
o Psammomatous melanotic schwannomas
o Cutaneous/Cardiac Myxomas
19
Q
Muir Torre
- Inheritance and Gene
A
o Inheritance – AD
o Gene – MSH2/6, MLH1, PMS2 (mismatch repair genes – causes microsatellite instability)
20
Q
Muir Torre
- Clinical and ?Tumour RIsk
A
o Multiple sebaceous lesions and keratoacanthomas
Tumour Risk
o Colon adenocarcinoma
o Less commonly: GU, lung breast, hematological
21
Q
Cowden Syndrome
- Inheritance/Gene
Jain
A
o Inheritance – AD
o Gene – PTEN (encodes tyrosine phosphatase protein – mutation causes proliferation)
22
Q
Cowden Syndrome
- Clinical Features/Tumour Risk
Jain
A
Clinical o Multiple trichilemmomas o Cobblestone mucosa (incl tongue – oral papillomas) o Acral keratoses Tumour Risk o Breast Fibroadenoma o Colonic polyps o Breast/thyroid (follicular) Ca
23
Q
MEN1 Syndrome
- Inheritance/Gene
Jain
A
(Wermer Syndrome)
AD
MEN1 (menin - tumour suppressor)
24
Q
MEN1 Syndrome
- Clinical Fx (nonmalig and malig)
Jain
A
Clinical – Non-malignant o Angiofibromas o Collagenomas o Lipomas o CALMs Clinical – Malignant o Pituitary o Parathyroid o Pancreatic
25
MEN2A Syndrome
- Inheritance/Gene
Jain
(Sipple Syndrome)
AD
RET (Tyrosine kinase receptor)
26
MEN2A Syndrome
- Clinical Fx (nonmalig and malig)
Jain
```
Clinical – Non-malignant
o Genital Lentigines
o Lichen or Macular Amyloidosis
o Haemangiomas
o Hamartomas
o Lipomas
Clinical – Malignant
o Thyroid Medullary (also MEN2B)
o Parathyroid
o Pheochromocytoma
```
27
MEN2B Syndrome
- Gene/Inheritance
Jain
(Multiple Mucosal Neuroma Syndrome)
AD
RET Mutation
28
Noonan Syndrome with Multiple Lentigines (LEOPARD)
- Gene/Inheritance
Jain
```
AD
PTPN11 mutation (encodes tyrosine phosphatase Shp2)
```
29
Noonan Syndrome with Multiple Lentigines (LEOPARD)
- Clinical Fx
Jain
```
o Lentigines
o ECG Abnormalities
o Ocular hypertelorism
o Pulmonary Stenosis
o Abnormal genitalia
o Retarded growth
o Deafness
```
30
Peutz-Jeghers Syndome
- Gene/Inheritance
Jain
o Inheritance – AD
| o Gene – STK11/LKB1 gene mutation – encodes serine-threonine kinase tumour suppressor
31
Peutz-Jeghers Syndome
- Clinical Fx/Tumour Risk
- ? Benign condition - clinically similar
Jain
Clinical
o Hyperpigmented macules lips/oral mucosa/fingers (starts in infacy/childhood)
o Intestinal Polyps (can have bleeding and intussusception)
Tumour Risk
o Increased risk GI Malignancy + Other Solid Organ Malignancies
Laugier-Hunziker Syndrome
- pigmented macules on lips, buccal mucosae, genitals, other mucosae
- Melanonychia in 50%
- no incr cancer risk
32
Gardner Syndrome
- Gene/Inheritance
Jain
AD
| APC encodes tumour suppressor gene (ras proto-oncogene)
33
Gardner Syndrome
- Clinical/Tumour RIsk
Jain
```
Clinical Fx
o Epidermoid Cysts
o Osteomas (mandible and maxilla)
o Supernumery teeth
o Odontomas
o Fibromas
o Congenital hypertrophy of retinal pigment epithelium CHRPE
Tumour Risk
o GI adenocarcinoma (inevitable)
o Osteochondromas
o Thyroid papillary ca
o Hepatoblastoma
o Adrenal Adenomas
```
34
Birt Hogg Dube
- Gene/Inheritance
Jain
o Inheritance – AD
| o Gene – FLCN (folliculin)
35
Birt Hogg Dube
- Clinical/Tumour Risk
Jain
Clinical
o Multiple fibrofolliculomas, trichodiscomas, acrochordons (facial, scalp, neck, upper trunk)
o Multiple pulmonary cysts (risk of spontaneous pneumothorax)
Tumour Risk
o Renal Cell Carcinoma (Rook says ‘various types’)
36
TSC
- Inheritance/Gene
Jain
AD
| TSC1 (hamartin) and TSC2 (tuberin)
37
TSC
- Diagnostic Criteria
Rook
Major features
Facial angiofibromas or forehead plaque
Non‐traumatic ungual or periungual fibroma
Hypomelanotic macules (more than three)
Shagreen patch (connective tissue naevus)
Multiple retinal nodular hamartomas
Cortical tuber
Subependymal nodule
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Lymphangiomyomatosis
Renal angiomyolipoma
Minor features
Multiple randomly distributed pits in dental enamel
Hamartomatous rectal polyps
Bone cysts
Cerebral white matter migration lines
Gingival fibromas
Non‐renal hamartoma
Retinal achromic patch
‘Confetti’ skin lesions
Multiple renal cysts
Definite TSC: either two major features or one major feature with two minor features
Probable TSC: one major feature and one minor feature
Possible TSC: either one major feature or two or more minor features
38
TSC
- Clinical Fx/Tumour Risk
(Dx criteria on separate card)
Jain
```
Clinical
o White ovoid or Ash-leaf macules (earliest finding)
o Facial angiofibromas
o Connective tissue naevi (Shagreen patches)
o Fibromas (periungal/subungal/gingival)
o CALMs
o Dental enamel pits
o Seizures
Tumour Risk
o Renal angiomyolipomas
o Retinal Hamartomas
o Pulmonary lymphangioleiomyomatosis
o Cortical Tubers
o Cardiac Rhabdomyoma
```
39
```
Werner Syndome (Adult Progeria)
- Gene/Inheritance
```
Jain
o Inheritance – AR
| o Gene – RECQL2 mutation (WRN gene), encodes RecQ DNA helicase -> genomic instability (incr aging and cancer)
40
```
Werner Syndrome (Adult Progeria)
- Clinical Fx
```
Jain
```
Clinical
o Normal Growth until teens, then
o Short stature/thin limbs
o Graying of adolescent hair
o Central obesity
o Pinched facial expression
o Beaked nose
o Micrognathia
o High pitched voice
o Mottled hyperpigmentation
o Sclerodermoid changes
o Cataracts
o DM
o Premature atherosclerosis
o Chronic leg ulcers
Tumour risk
o Soft tissue sarcomes
o Osteosarcoma
o SCC
```
41
Progeria (Hutchinson-Gilford Syndrome)
- Gene/Inheritance
Jain
o AD
| o Gene – Lamin A mutation (LMNA), encodes lamin A and C (nuclear envelope protein
42
Progeria (Hutchinson-Gilford Syndrome)
- Clinical Fx
Jain
```
Clinical Fx
o Marked premature aging (median lifespan 12)
o Large cranium, frontal bossing, prominent scalp veins
o Beaked nose
o Micrognathia
o ‘plucked bird’ appearance
o Loss of subcutaneous tissue
o Sclerodermoid skin
o Alopecia
o High pitched voice
o Average intelligence
o Severe premature coronary atherosclerosis
```
43
Non-syndromic chronic mucocutaneous candidiasis
Jain/Bol
```
Non-syndromic CMC
o Genes: AD IL-17F mutation, AR IL17RA/C and TRAF3-interacting protein
o Oral thrush 6mo-2yo
o Cutaneous/nail involvement common
o No endocrinopathy
o Cutaneous Staph infections
```
44
APECED – Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome
(A CMC condition)
Jain/Bol
```
AIRE mutation, AR
Finns, Jews, Iranian, Sardinians
Mucocutaneous candida infections, mean age 3
Endocrinopathies
o Hypoparathyroidism/hypoadrenocortism
o Hypogonadism
o Thyroid disease
o T1DM
o Hypituitarism (eg GH def)
Other Autoimmune disorders
o Alopecia areata/vitiligo, urticarial, lupus-like panniculitis
o Pernicious anaemia
o Hepatitis
o Pneumonitis
o Sjogren-like syndrome
Other Fx
o Dental enamel hypoplasia
o Failure to thrive
o Chronic diarrhoea
o Keratoconjunctivits
o Hyposplenism
o Hypertension
o Oral/oesophageal SCC
```
45
Other Causes CMC
(not STAT1 or APECED)
- Incl immundef and metabolic
Jain/Bol
CMC Plus susceptibility to mycobacterial organisms
CARD9 assoc CMC
Dectin-1 deficiency
Chronic localised candidiasis (candidal granuloma)
Late onset CMC
Familial chronic nail candidiasis
CMC assoc with other immunodeficiencies
o Hyper IgE due STAT3 & DOCK8 deficiencies
o SCID
o DiGeorge
o IL-12Rbeta1 and IL-12B deficiency
o AD hypohidrotic ectodermal dysplasia with immunodef (NFKBIA mutation)
o KID
CMC assoc with metabolic disorders
o Multiple carboxylase deficiency
o Acrodermatitis enteropathica
Ectodermal-dysplasia-ectrodactyly clefting syndrome
46
Treatment approach CMC
Jain/Bol
Infatile thrush is common, esp post Abs (eg recurrent OM episodes)
o Clearance post traditional therapy indicates 2ndry vs CMC
o CMC do not respond well to standard topicals – need long term itra/fluconazole
o Fluconazole resistant candida may need posaconazole, voriconazole, echinocandins
If recurrent/recalcitrant
o Consider ruling out HIV
o Adjunctive therapy with G-CSF may incr IL-17
o Nail avulsion, abscess drainage, debridement of thick plaques
o If STAT1 mutations – JAK inhibitors eg ruxolitinib may be of help
o If APECED – monitor annully for endocrinopathy/autoimmune manifestations
47
HIES
- types/genes/inheritance
Jain/Bol
- Inheritance/Gene
o AD – (signal transducer and activator of transcription 3) STAT3 – critical to IL6 (pyrogen/acute phase) & IL10 (anti-inflammatory cytokine), downregulates osteoclast diff – leads to OP, downregulation leads to incr IFNgamma and TNF
o AR – DOCK8 biallelic mutation – leads to incr Th2 cells and IL31, decr Th1 and Th17 (TYK2 in Jain but Bol says only risk of infections, not HIES)
- Incr risk of Non-Hodgkin Bcell Lymphoma
- Up to 50% AR-HIES die by age 20 from infection, malig, CNS
48
HIES
| - clinical AD vs AR
Clinical – AD-HIES STAT3
o Incr IgE Levels and peripheral eosinophilia
o Cold abscesses – large skin/subcut abscesses without great inflammatory response
o Coarse Facies
o Eczema, frequently clears by adolescence, not assoc with other atopic features
o LRTIs/bronchiectasis (staph/haemoph inf/PJP)*
o High arched palette/Retained primary teeth
o Pneumatocoele
o Otitis media
o Osteopenia with recurrent fractures, minor trauma (common in adolescence 50%+)
o Reports of Chiari malformation/lacunar infarcts/focal hypodensities
Clinical – AR-HIES DOCK8
o Incr IgE Levels and peripheral eosinophilia
o Cold abscesses – large skin/subcut abscesses without great inflammatory response
o Eczema
o LRTIs
o Otitis media
o Asthma, Food allergies/Anaphylaxis/Autoimmunity
o Cerebral vasculitis
o Mucocutaneous SCC and Lymphoma
49
HIES
- Ix/Rx
Bol
Ix
Marked elev IgE >2000 & peripheral eosinophilia
Serum Igs and lymphocyte subsets normal in classic HIES
DOCK8 def
o Lymphopenia
o Low CD4/8/B cell subsets
o Low IgM, Variable IgG
Treatment
Lesion/abscess management
o I&D, ?prophylactic Abs
o IFNgamma can control infections
o IVIg can lower IgE, improve dermatitis, prevent infections
o Anecdotally omalizumab can help with dermatitis
50
SCID/Omenn
- Genetics
- Clinical
- Ix/Dx
- Rx
Jain/Bol
XLR (40%) – deficiency of gamma chain IL2RG
AR – defect in JAK3 or adenosine deaminase ADA or IL7R (5-15% each)
Heterogenous group of disorders – impaired humoral and cellular immunity
Characterised by deficient (or absent circulating lymphocytes)
ADA deficiency – pts at risk of multiple DFSP in first two decades
Death by 1yo if no Rx (diagnose before live vax!)
Variable widespread eruption, classically sebderm-like/morbilliform (like maternofetal GVHD)
Can also look like lichen planus, acrodermatitis enteropathica, ichthyosiform erythroderma, systemic sclerosis
Recurrent infections (CMC, viral gastro, pneumonias incl PJP, skin)
No tonsils/lymph node tissue
Chronic diarrhoea
FTT
Omenn Syndrome
o Exfoliative erythroderma, alopecia
o LAD, HSM, diarrhoea, peripheral eos/leuks++, elev IgE
Maternal Tcells >1% of periph Tcells in SCID, usually asyptomatic though can produce rash/LFTs/eosinophilia
Histo of Omenn like GVHD (incl necrotic keratinocytes), though with acanthoses, paraK, Tcell dermal infiltrate
Low lymphocyte count
ADA def shows cupping and flaring of costochondral junction on XR
Need to excl HIV (would have nomal Igs)
Part of newborn screening in US, not here
Isolation
IVIg and PJP prophylaxis
HSCT
Counselling for parents – can be screened for prenatally
51
Wiskott Aldrich Syndrome
Jain/Bol
General
o Inheritance – XLR
o Gene – loss of funct WASP gene (encodes WAS protein – assembles actin filaments)
o Characterised by low platelets (<70000/mm3) and platelet dysfunction from birth
o Increase risk of lymphoma (NHL), mean 10yo in15% untreated
o Death from Infection>haemorrhage>malignancy (~15yrs without HSCT)
o Main Rx – Bone Transplant
Clinical
o Petechiae/ecchymoses
o Epistaxis, melaena, haematemesis, haematuria
o Atopic Dermatitis (face/scalp/flexures), excoriated with crust/petechiae
o Recurrent Bacterial Infections (from 3/12 w diminishing maternal Abs, encapsulated bact – strep pneu, H inf, N menin, later PJP+viruses)
o LAD/HSM
o Assoc autoimmune disease common (SVV w/painful oedema, cytopenias, arthritis, IBD, cerebral vasculitis, food allergy, asthma, urticaria)
```
Ix/Dx
o Platelets <70000/mm3 & low vol <5fL
o Low lymphocytes/eosinophils
o IgM and IgG2 low (oMG LOW)
o IgE/A/D (Hi DEA) high
```
Rx
o Topical Steroids for Dermatitis
o Prophylactic Abs
o HSCT – should normalise platelets/infection risk (>90% surv rate, lower if unrelated/>5yo)
o Systemic Steroids/Immunosupps eg Ritux for Autoimmune
o Prenatal Dx avbl (esp important for sisters/female relatives)
52
OCA Type 1a
Jain/Bol
Gene/Inheritance – AR/TYR – leads to tyrosinase enzyme def
Type 1 (a+b) most frequent OCA worldwide
Clinical
o No melanin skin/hair/eyes (may go yellow over time)
o Milky white-pink skin
o Blue-gray eyes
o Amelanotic naevi (pink)
o Extreme UV sensitivity
o Incr Skin Ca
o Neurological – nystagmus, strabismus, decreased visual acuity (many legally blind)
53
OCA Type 1b
Jain/Bol
General
o AR/TYR (same as Type 1a)
o Aka yellow/minimal pigment/platinum/temperature sensitive OCA
```
Clinical
o Little-no pigment at birth, develop some in 1st/2nd decades
o Burn without tan
o Iris translucency
o Amelanotic/pigmented naevi
```
‘Temp sensitive’
o Abnormal tyrosinase loses activity at 35deg (works in cooler areas) – like a Siamese cat
o No pigment at birth
o Puberty -> arm hairs red brown, leg hair dark brown
54
OCA Type 2
Jain/Bol
General
o AR/P gene (decr eumelanin synthesis) – brown OCA
o Most common OCA in Africans
o Majority of africans with OCA pos have OCA2
o Hypopigmentation in Prada Willi and Angelman Syndrome a form of OCA1 (1% of each syndrome OCA2 – deletion of one P gene and mutation of the other)
Clinical
o Broad phenotype (minimal to mod dilution)
o Pigmented naevi over time
o Light brown hair/skin
55
OCA Type 3
Jain/Bol
General
o TYRP-1 (tyrosinase-related protein 1), AR inheritance
o ‘rufous’ (classic type) or ‘brown’ type (rarely desc, brown more often OCA2)
o Type III-V skin colour
Clinically
o Red-bronze skin colour, ginger red hair
o Blue/brown irides
o Nystagmus, decr VA
56
OCA Types 4-7
Bol
```
OCA Type 4
OCA4
General
o SLC45A2 gene
o Most common in Japan/China/India, infrequently 5% in Caucasians
Clinical
o White to yellow or brown
o May/may not develop pigmentation of skin/hair over time
```
OCA5
o Consanguineous Pakistani Family – White skin, golden hair.
OCA6
o China/French Guiana
o White to light brown skin, some tanning
o Yellow hair at birth that darkens
OCA 7
o Faroe Islands of Denmark
o Lighter skin than relatives, light yellow to brown hair
57
Chediak-Higashi Syndrome
Jain
General
o Disorder of Melanosome transport/transfer
o Consider like an OCA with immunological problems
o Inheritance – AR
o Gene – LYST/CHS1 (lysosomal trafficking regulator), defect in vesicle trafficking
o Giant intracytoplasmic granules (melanocytes, platelets, leukocytes)
```
Clinical
o Onset in infancy
o Oculocutaneous albinism with immunological deficiency, slate grey skin colour
o Silvery metallic hair (melanin clumps)
o Recurrent infections
o Easy bruising
o Progressive neurological deterioration
o “accelerated phase” – pancytopenia, lymphohistiocytic infiltration of the reticuloendothelial system
```
Treatment
o Stem Cell Transplantation
58
Hermansky-Pudlak Syndrome
Jain/Bol
General
o Disorder of Melanosome biogenesis
o Inheritance – AR (10 different types but all AR)
o Genetics – HPS gene mutation (lysosomal transport protein) or AP3B1 (forming vesicles/protein trafficking)
o Consider OCA with haemorrhagic diathesis (absent dense bodies in platelets) and granulomatous colitis
```
Clinical
o OCA
o Haemorrhage – epistaxis, menorrhagia*
o Pulmonary fibrosis*
o Granulomatous colitis*
o Less often - Renal failure & Cardiomyopathy
```
Treatment
o Pulmonary fibrosis main cause of prem death (30-50yo) ?pirfenidone contradictory evidence
o Platelet transfusions prior to surgery
59
Griscelli Syndrome
Jain/Bol
General
o Disorder of melanosome transport or transfer
o Inheritance – AR
o Gene – GS1: myosin Va, or GS2: Rab27a – encodes GTPase (rab family), GS3 - MLPH
Clinical
o Variable Pigmentary Dilution
o Silvery metallic hair
o Neurological involvement (moreso GS1 – MYO5a expressed on neurons)
o Immunodeficiency (GS2 – defective release of lysosomal contents from haematopoietic cells, widespread macrophage/Tcell activation leading to death – CNS involvement secondary) – recurrent pyogenic infections, pancytopeniadary)
Ix
o Uneven clumps of melanin in medulla of hair on microscopy, no giant melanosomes
Rx
o HSCT for GS2 only (not 1 or 3)
60
Incontinentia Pigmenti
General, Genetics, Clinical (incl associations)
Jain/Bol
General
o Defect in melanosome transfer
o Inheritance – XLD
o Gene – IKBKG mutation, encodes NEMO protein (NF-kb Essential MOdulator)
o Usually antenatally lethal in males (F:M 20:1) – boys: Klinefelter syndrome or half chromatid/poszygotic mutation (often limited disease)
Clinical – Four stages + other associations
o Vesicular – vesicles in linear/whorled streaks
o Verrucous – hyperkeratotic linear plaques
o Hyperpigmented - linear/whorled hyperpigmentation (name related to dermal melaophages)
o Hypopigmented – hypopigmented thin streaks
Associations – other ectodermal abns
o Linear absence hair – often at vertex (30-40%) and sweat glands
o Missing or conical teeth (40-50%)
o Dystrophic Nails (ridging/pitting>subungal keratoses, 10-20%)
o CNS abnormalities (seizures, developmental delay)
o Ocular disease (retinal vascular anomalies, blindness)
61
Incontinentia Pigmenti
Pathology, Diagnosis/Ix, Management
Jain/Bol
Pathology
o Early inflammatory – eosinophilic spongiosis, scattered dyskeratotic keratinocytes
o Verrucous lesions – acanthosis, hyperkeratosis, focal dyskeratosis
o Hyperpigmented – pigmentary incontinence, variable vacuolation of keratinocytes
o Hypopigmented – thinned epidermis, lack of dermal adnexae
Diagnosis/Ix
o Distinguish from infection (though child usually very well and clinically distinct)
o Peripheral eosinophilia/leucocytosis common in neonates
o Histo can confirm
o Linear naevoid hyper-/hypo-pigmentation – no inflammation, hypigmentation epidermal, adnexae normal
```
Management
o Ophthalmology involvement
o Baseline neurological evaluation
o Dental assessment
o Examine the mother (look for atrophic streaks)
o Refer for genetic counselling
```
62
DDx for Scalp Poliosis
Inflammatory
- Vitiligo/AA(initial)
- Halo Nevus
- Postinflammatory (eg DLE, blepharitis)
- Postinfectious (eg VZV)
- Post-traumatic
- Vogt-Koyanagi-Harada Syndrome
- Alezzandrini Syndrome
- Melanoma-assoc leukoderma (spont or immunotherapy)
Inherited
- TSC
- Piebaldism (midline frontal)
- Waardenburg Syndrome (primarily midline frontal)
- Isolated white forelock (?separate/forme fruste piebaldism)
- Isolated occipital white lock (XLR)
- White forelock with osteopathia striata (AD or XLD)
- White forelock with multiple malformations (AD or XLR)
- NF1 - overlying a neurofibroma
Nevoid
- Angora Hair Nevus
- Naevus Comedonicus Assoc
- Scalp heterochromia secondary to mosaicism
Pharmacological
- Imiquimod
- lantanoprost (eyelash poliosis)
- tyrosine kinase inhibitors (eg cetuximab)
Idiopathic
63
Piebaldism
Jain/Bol
General
o A form of hereditary hypomelanosis
o Defective melanocyte migration and development
o Poliosis and areas of congenital, stable, circumscribed leukoderma due to absence of melanocytes
o Inheritance – AD
o Gene – KIT proto-oncogene mutation, tyrosine kinase receptor family (need KIT receptor for dev of melanocytes – before migration from neural crest and postnatally)
o 1:40,000
Clinically
o White forelock (poliosis) 80-90%
o Irreg leukoderma (favour ant trunk, extremities, forehead), incl hairs, normally pigmented/hyperpigmented macules typically apparent within (and can occur outside leukoderma too)
o Leukoderma spares hands/feet/hips/shoulders
o Otherwise healthy
Dx/Management
o Clinical diagnosis, usually apparent
o Need to excl Waardenberg Syndrome – Ophthal Review, Hearing Assessment
o Cosmetic camouflage and sun protection
o Can trial autografting into areas of leukoderma – multiple procedures
64
Waardenberg Syndrome
Jain/Bol
General
o Disorder of melanocyte development
o Rare disorder, mostly AD, 1:50-200,000, M:F, all races
o Four main types
o Features centred around piebaldism with extra
WS 1
o AD, PAX3 (transcription factor) mutation
o White Forelock/Leukoderma
o Heterochromia iridis
o Synorphrys (medial eyebrow hyperplasia) + broad nasal root
o Dystopia canthorum (dist btw med canthi widened, interpupillary dist normal)
o Congenital Deafness Uncommon in WS1
WS 2
o AD, MITF (transcription factor) mutation
o WS1 features, deafness common, though no dystopia canthorum
WS 3
o AD, PAX3 mutation
o WS1 + upper limb abnormalities (hypoplasia, syndactyly, flexion contractures)
WS 4
o AD SOX10 (transcription factor), also AR (endothelin 3 EDN3 or endothelin receptor EDNRB)
o WS1 + Hirschprung disease and Deafness common, broad nasal root/dystopia canthorum uncommon
Management
o Clinical diagnosis, examine the family
o Refer for audiological assessment/management
o Genetic counselling
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McCune Albright Syndrome
Bol/Jain/Ali
General
o Aka Polyostotic Fibrous Dysplasia
o Sporadic Mutation in GNAS1 (encodes alpha subunit of Gs adenylate cyclase)
o Don’t confuse with Albright hereditary osteodystrophy (same gene)
Clinical
o Large blocks of café au lait macules (geographic/Coast of Maine border)
o Endocrine Abns, usually precocious puberty, also hyperparathyroid, hyperthyroid, acromegaly, hypophos rickets, infantile cushings
o Polyostotic fibrous bone dysplasia (often under CALM, pres bone pain, deformity, path fracts)
o Base of skull sclerosis
o MCCune – Café au Lait, precocious puberty
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Cronkhite-Canada Syndrome
Bol/Ali
Disorder of hyperpigmentation – lentiginosis, typically older men
Clinical
o Lentigines of hands/feet/buccal mucosa
o Nail dystrophy
o Alopecia (diffuse, non-scarring)
o Assoc with intestinal polyposis, diarrhoea, malabsorption
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Dowling-Degos Disease
Bol/Ali
General
o Uncommon, Inheritance AD
o Mutation in Keratin 5 (also assoc EBS with mottled pigmentation)
o Onset in adulthood 20s-30s
o Galli Galli Disease – a variant with suprabasilar acantholysis
Clinical
o Reticulated hyperpigmentation axilla and groin, can involve gluteal/inframammary/neck/torso/inner thighs
o Comedone-like lesions on back/neck, pitted perioral scars, epidermoid cysts, HS also reported
Histo Pearls
o Incr pig basal layer – ‘antler-like’ pattern with finger-like rete ridges
o Dermal melanophages, superficial perivascular lymphohistiocytic infiltrate
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Ichthyosis Vulgaris
| - Genetics/Onset/Pathogenesis
Inheritance
o Autosomal Semi-dominant (mild if heterozygous)
o Gene FLG
Incidence
o 1:250-2000
o M=F
Age at presentation
o 3/12 to 12/12
Pathogenesis
o Retention hyperkeratosis, normal epidermal prolif
o Defect in profillagrin synth less profillagrin in keratinocytes (likely polygenic disease)
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Ichthyosis Vulgaris
- CF/Mx
Bol/Ali/Spitz
CF
o Fine white adherent scale, pref extensor surface extremities
o Spares flexures
o Face usually spared but can involve cheeks/forehead
o AD >50%
o KP
o Accentuated palmoplantar markings, rarely frank keratoderma
DDx
o AD, Xerosis, Acquired Ichthyosis, X-linked ichthyosis, Lamellar ichthyosis
Ix
o Skin Bx – Anterior Shin - absent granular layer
o EM – small poorly formed keratohyaline granules
Mx
o Emollients, care re Salicylism, systemic retinoids rarely warranted
Prognosis
o Improves with age
o Will be better in warm/humid environments
Pearl
o Hard Dx to make.
o No characteristic CF, abs gran layer only in minority.
o Inadequate endog humectant Urea/alpha hydroxyl acid emollients work well
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XL Ichthyosis
- Genetics/PrenatalDx/Presentation/Pathogenesis
Bol/Ali/Spitz
Inheritance
o X-linked recessive
o STS gene Xp22.32 (gene deletions most common – 90%, contiguous deletion syndrome – 10%)
Prenatal Dx
o Amnio/CVS – steroid sulfatase assay, DHEAS levels
o DNA Analysis
o Maternal estriol (serum/urine) and DHEA Levels
Incidence
o 1:2000 – 1:6000 MALES
Presentation
o Two to six weeks old
Pathogenesis
o Steroid Sulfatase gene deletion -> steroid sulf activity in stratum corneum -> incr cholesterol sulfate and decr chol levels -> may play a role in hyperkeratosis
o Contiguous deletion syndrome -> may result in
- Kallman Syndrome
- X-linked recessive chondroplasia punctate
o Labour: failure to progress due to decr placental sulfatase and oestrogen, and incr fetal DHEAS
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XL Ichthyosis
- CF/Ix/Mx
Bol/Ali/Spitz
CF
o Skin
- Brown adherent scale, incr on extensors, post neck/trunk, SPARES flexures/palms/soles/face
o Eyes
- Comma-shaped corneal opacities
- Asymptomatic – 50% adult males, some female carriers)
o Obstetric
- Plac sulfatase deficient – failure of labour to begin/progress (in mother with affected fetus
o Genitourinary
- Cryptorchidism (20%), with assoc increased risk of testicular cancer. (incr rick REGARDLESS of cryptorchidism)
```
DDx
o Ichthyosis Vulgaris
o Epidermolytic hyperkeratosis
o Lamellar Ichthyosis
o Contiguous gene syndromes
```
Ix
o Steroid sulfatase activity in scales, fibroblasts, leucocytes
o Lipoprotein electrophoresis – incr mobility of LDL
o Serum chol sulf levels -> increased
o Histo: Retained corneodesmosomes in the stratum corneum
```
Mx
o Gen paeds – full clinical examination
o Dermatologist – emollients
o Paed urologist
o Obstetrics – potential complications
```
Prognosis
o Waxes and wanes throughout life – seasonal variation
Spitz
o All need check for undesc testes and testicular Ca. Onset can be variable (eg cradle cap ++ at birth then nothing until 4-5 years of age). Can be bad during winter and virtually nothing during summer. AHAs!
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Epidermolytic Ichthyosis (Bullous CIE)
Bol/Ali
General
o Inhertance – AD
o Genes – KRT1 & KRT10 (both expressed in differentiated spinous & granular layers, KRT1 more palmoplantar than KRT10)
o Mutations interfere with keratin alignment, oligomerization, filament assembly
o Presents at birth
Histology
o ‘epidermolytic hyperkeratosis’ differentiates from other ichthyoses (orthokeratotic hyperkeratosis, acanthosis, hypergranulosis, cytolysis of suprabasal and granular layers)
o Similar to epidermolytic PPK (though limited to palms and soles)
```
Clinical – at Birth
o Erythroderma
o Blistering and erosions
Clinical – Later
o Generalised or localised
o Hyperkeratosis, cobblestone pattern (prominent over joints) & flexural ridging (sometimes like Ich Hyst Curth-Macklin, does not have bullae/epidermolysis)
o Variable erythroderma
o Palmoplantar involvement
o Blistering and bullae
```
Assoc clinical features
o Frequent skin infections
o Malodour (big issue)
o Gait/posture abnormalities
Management
o Neonates – ICU, isolation, prevent infection/dehydration/electrolyte issues, protective padding/lubricants
o Keratolytics cont ureas, sal acid, AHAs – poorly tolerated in children (stinging)
o Top tretinoin/Vit D (may irritate)
o Emollients/humectants with gentle mechanical abrasion
o *Oral retinoids may increase fragility*, start low dose with gradual increase
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Superficial epidermolytic ichthyosis
Bol/Ali
```
General
o Aka Ichthyosis Bullosa of Siemens
o Inheritance – AD
o Gene – KRT2 (only expressed in the uppermost spinous/granular layers)
o Milder than EI
```
Histological
o Orthokeratotic hyperkeratosis, acanthosis
o Vacuolization/cytolysis of the granular layer -> occasionally leads to sup intraepidermal separation
Clinical – At Birth
o Variable erythroderma and superficial blisters
o Trauma induced small blisters can occur on extremities in early infancy, but subside with hyperkeratosis onset
Clinical – Later
o Ridging/shiny/lichenified skin circa joints/flexures/dorsum of hands/feet
o Palms/soles spared
o Characteristic feature – sup denuded areas with collarette-like borders (from sup blister shedding)
Dx
o Peeling skin syndromes and EBS can look similar – don’t have granular vacuolisation or hyperkeratosis, and EBS would have deeper blisters
Mx
o Same as EI/Bullous CIE
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Ichthyosis en confetti
Ali/Bol
General
o Rare, Inheritance – AD
o Gene – KRT10 (Ichthyosis and PPK), less oftern KRT1
Clinical – Birth
o Erythroderma and scaling w/ PPK
Clinical – Later
o During childhood, hundreds to thousands of small confetti-like islands of normal skin appear, more with time (revertant mosaicism – each confetti spot represents a revertant clone)
Associated features
o Joint contractures
Histology – loss of epidermal differentiation above basal layer:
o Acanthosis
o Perinuclear vacuolisation of keratinocytes in upper epidermis
o Parakeratotic hyperkeratosis
o Revertant skin - normal
75
Ichthyosis hystrix Curth Macklin
General
o Inheritance – AD
o Gene – KRT1 (frameshift mutation, different to EI)
o Similar to Epidermolytic Ichthyosis, but no skin fragility
o Variable expression even within families
Clinical – Birth
o Hyperkeratosis can be present at birth, or in early childhood
Clinical – Later
o Mild to severe/mutilating PPK
o Hyperkeratotic plaques – verrucous/cobblestone/hystrix-like pattern on extremities and trunk
o Pseudoainhum, digital contractures, knuckle pads, starfish-like keratoses (all sometimes)
Histology
o Orthokeratotic hyperkeratosis, hypergranulosis, acanthosis, church-spire-like papillomatosis (all non-spec)
o Bi-nuclear or vacuolated cells in differentiated layers
o Shell-like network interspersed network of KIFs assoc with perinucleated vacuolisation and formation of binucleated cells
o Cf EI – no epidermolysis or keratin clumping
Rx
o Keratolytics and systemic retinoids, similar to EI
