Genoderms Flashcards

Question

Lamellar ichthyosis clinical

Answer 1

- 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

Answer 2

``` Dx: - Transglutaminase-1 expressor Management: - Neonate --> NICU, high humidity chamber, emollient - Later: retinoid/emollient ```

Answer 3

- Autosomal recessive | - 1 in 50 000

Answer 4

- 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

Answer 5

1. Cutaneous 1. Neonate: erythroderma (similar to CIE) and continuous peeling of skin. At risk of electrolyte imbalances, failure to thrive, pneumonia, sepsis. 2. Gradually evolves into serpiginous or circinate scaling and erythematous plaques --> ichthyosis linearis circumflexa which are double-edged scale, trunk and extremities, pruritic 3. eczematous plaques in flexures 4. scalp can have thick scale 2. Hair shaft abnormalities 1. Usually improves with age 2. Trichorrhexis invaginata is bamboo hair --> ball and socket appearance 3. Can also have pili torti (flat and twisted), trichorrhexis nodosa (weak spots that causes it to break), helical hair 3. Immune dysregulation 1. Atopy, and immunodeficiency involving memory B cells and natural killer cells 2. High IgE 3. Eosinophilia and allergy to foods and other antigens is common --> urticaria, angioedema 4. Increased IL-17 5. Recurrent lung and skin infections 6. Increase in SCCs and BCCs in 30s 4. Extra: 1. Failure to thrive when a child due to enteropathy with villus atrophy

Answer 6

- 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

Answer 7

- SPINK5 --> can be prenatal in CVS or amniocentesis | - Immunostain: anti-LEKTI antibodies

Answer 8

- CIE - Erythrodermic psoriasis - Primary immunodeficiencies - Wiskott Aldrich, Omenn, IPEX - AD-hyper IgE syndrome --> high IgE, eczema, neonatal papulopustular eruption - Acrodermatitis enteropathica - Peeling skin syndromes

Answer 9

- 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

Answer 10

- 1/100 000 to 1/30 000 - M=F - Autosomal dominant with complete penetrance

Answer 11

- 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

Answer 12

- 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

Answer 13

- Salivary glands: painful swelling - Neuropsychiatric: epilepsy, intellectual impairment, mood disorders, bipolar, schizophrenia --> not fully established - Ocular: corneal ulcerations

Answer 14

- 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

Answer 15

- 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

Answer 16

- UV exposure - Sweating, heat, occlusion - Medications: lithium

Answer 17

- 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)

Answer 18

- 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

Answer 19

- 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)

Answer 20

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

Answer 21

- 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

Answer 22

- 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

Answer 23

- 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

Answer 24

- 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

Answer 25

- 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

Answer 26

- 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

Answer 27

- Loss of intercellular bridges widespread in the epidermis - 'dilapidated brick wall' - dermal papillae, lined by a single layer of basal cells, protrude into blister cavities and referred to as 'villi' - necrotic keratinocytes are uncommon - Chronic: epidermal hyperplasia, parakeratosis, focal crusts - Peri-vascular lymphocytic infiltrate

Answer 28

- Dariers - Infectious: intertrigo, candidiasis - Irritant dermatitis, LSC - Inverse psoriasis - Pemphigus vegetans or pemphigoid vegetans

Answer 29

- General measures: - lightweight clothes - avoid adhesive dressings - antimicrobial cleansers - topical/systemic antibiotics - Topical and intralesionals - Topical steroids - Injection of steroids - low potency - Topical calcineurin inhibitors - Topical 5-FU and vitamin D analogues - Botox injections - Zinc oxide paste - Surgical - Wide excision with grafting - Superficial ablative techniques - Well documented: dermabrasion, laser vaporization of the epidermis (erYag) and PDT - Removal of diseased epidermis plus dermal niche of fibroblasts is recommended - Re-epithelialization occurs within 7-14 days - Systemic treatment - Doxycycline - Oral acitretin or isotretinoin - Anecdotal: pred, cyclosporin, MTX, dapsone, afamelanotide - Low dose naltrexone - good at low dose 4.5 mg daily, variable when higher. Recommend adding glycopyrrolate as well

Answer 30

- 1/3000 | - Autosomal dominant, NF1 mutation

Answer 31

- NF1 mutation, autosomal dominant - On chromosome 17q11 - NF1 encodes neurofibromin - over 80% have a mutation that predicts truncation of the neurofibromin protein, and 5% have a large deletion - Those with the deletion - Type 1 deletion --> more severe phenotype, increased risk of malignant peripheral nerve sheath tumours, cognitive deficiencies, facial dysmorphism, overgrowth and connective tissue dysplasia - Somatic second hit mutation inactivating the remaining allele of the gene can be found within skin lesions of NF1 - 30-50% have no affected relatives - Penetrance is nearly 100%, but expressivity is variable - NF1 Schwann cells oversecrete stem cell factor --> which binds the Kit receptor on NF1 heterozygous mast cells, resulting in mast cell recruitment and their activation to produce growth factors that stimulate neurofibroma development - Imatinib can inhibit Kit signaling and is being investigated for NF1

Answer 32

Diagnostic criteria: CANFOOL - 2 or more of the following: - CALM 6 or more - Axillary or groin freckling - Neurofibromas X 2 or plexiform neurofibroma X 1 - Family history - Optic glioma - Osseus lesion - sphenoid wing dysplasia or thinning of long bone cortex - Lisch nodules - 2 or more

Answer 33

- Cutaneous - Neurofibromas - 80% - CALM >90% - Axillary or inguinal freckling ~80% - Plexiform neurofibroma - Naevus anaemicus 30-50% - JXG - 15-35% in first 3 years o life - Ocular - Lisch nodules ~ 90% by 20 years of age - Choroidal nodules- >80% - Neovascular glaucoma, retinal vasoproliferative tumours - Skeletal: - Cranial: macrocephaly (20-50%), hypertelorism (25%), sphenoid wing dysplasia - Spinal: scoliosis, spina bifida - Limbs: dysplasia of long bone cortex, pseudarthrosis - Generalised osteopenia and osteoporosis - Short stature - Pectus deformity (30-50%) - Tumours - Nerve and muscle: malignant peripheral nerve sheath tumours (3-15%), rhabdomyosarcoma - CNS: optic glioma (10-15%), other CNS tumours - Neck and chest: parathyroid adenoma, breast cancer (~5 fold increased risk in women <50 years) - Abdominal organs: phaeochromoctyoma (1%), duodenal carcinoid, somatostatinoma, GIST - Blood: juvenile myelomonocytic leukaemia - Neurologic - Unidentified bright objects on MRI - 50-75% - Learning difficulties - 30-50% - Seizures ~5% - Intellectual impairment - Aqueductal stenosis and hydrocephalus - Cardiovascular - Hypertension ~30%, essential >renal artery stenosis - Pulmonic stenosis - Renal artery stenosis - Cerebrovascular anomalies

Answer 34

uniformly pigmented macules except for the scalp, palms and soles, when within areas of dermal melanocytosis can have a rim of normally pigmented skin. Those that are large and have hypertrichosis --> palpate to exclude possibility of an underlying plexiform neurofibroma. Need to have six. Must be >5 mm in pre-pubertal, and >15 mm in postpubertal

Answer 35

- Cutaneous: proliferation of spindle cells in the dermis. Skin coloured, pink, tan or brown papulonodules. Can be dome shaped or pedunculated, buttonhole sign. Can be pruritic. Can appear as early as 4-5 years of age. - Subcutaneous: deeper, firmer and less well-circumscribed. 1/5 have a subcutaneous, and 1/4 develop associated complications. Sometimes when so deep, need an MRI to find them. - Blue-red macules: thick-walled blood vessels as well as neurofibromatous tissue within the dermis - Pseudo-atrophic macules - replacement of collagen in the reticular dermis - Plexiform: track along nerves to create tender, firm nodules or masses. 'Bag of worms' consistency, or can infiltrate diffusely to involve various layers of the skin, fascia, muscle or internal structures. 25% have PNF. Can get ++ large ones that impinge on the head and neck or extremities, etc. Can have hypertrichosis and hyperpigmentation. - Malignant transformation in 3-15% to neurofibrosarcomas, peak incidence in young adults. Keep an eye out for increased firmness, rapid growth, persistent pain. They can be ++ aggressive and fatal

Answer 36

- 'Crowe's sign' - 1-3 mm brown macules in intertriginous zones, neck and groin - arise 4-6 years of age, following emergence of CALMS but before neurofibromas

Answer 37

- 15-35%, during first 2-3 years of life. - Have a 200-500 fold increased risk of developing juvenile myelomonocytic leukaemia - 'Triple association': NF1, JML and JXG --> neurofibromin known to regulate the proliferation of myeloid cells, but exact pathogenesis is unclear

Answer 38

naevus anaemicus and glomus tumours. Favour the trunk, especially the mid-chest, and become more evident after rubbing the skin. Glomus tumours develop more on fingers than toes, and present with pain and sensitivity to cold.

Answer 39

begin ~ 3 years of age, found in 90% of NF1. S1-2 mm dome shaped, yellow-brown papules. Pretty asymptomatic. Can also get choroidal nodules

Answer 40

- Optic gliomas. Vary variable - can cause vision problems. Precocious puberty 3% complication. - UBOs - 50-75%. Seen in basal ganglia, brainstem, cerebellum. They can evolve. - Learning difficulties - 30-50%, with increased risk of ADHD, headaches, sleep disturbances. Can have seizures ~5%.

Answer 41

- Macrocephaly, hypertelorism, scoliosis - Pseudarthrosis: very distinctive but not overly common, mostly of the tibia. Has bowing, then erosion of the bone cortex leading to a pathologic # and false joint formation (which is the pseudarthrosis). - Sphenoid wing dysplasia is congenital, typically unilateral bony defect --> may present as pulsating exopthalmos

Answer 42

- PNFs and skeletal defects are congenital, and then CALMs and naevus anaemicus become apparent in the first few years of life - Freckling, Lisch and optic gliomas occur in school age years - Multiple CNFs develop closer to puberty - Criteria met by 97% o patients by the time they're 8, and 100% by 20

Answer 43

present in one or more dermatomes, or in a mosaic distribution with midline demarcation. This is from postzygotic NF1 mutation. If it involves the gonads, there is a chance of full-blown NF1 in the patient's offspring

Answer 44

this is NF1-like, and is actually from SPRED1 gene. They have CALMS >6, intertriginous freckling, but they don't have most other cutaneous things, but they do have macrocephaly, learning disabilities, lipomas, etc.

Answer 45

- At diagnosis - Dermatology exam --> surgical consultation if concerned, PET-CT if concerned of malignancy - Ophthal exam --> orbital/brain MRI if concern of optic glioma - Ortho --> exam for scoliosis - Neuro exam - Cardiac --> murmur - refer to cardio - Pubertal development --> MRI and endo referral if precocious puberty - Ongoing monitoring for uncomplicated disease - all annual: - Derm evaluation --> PET-CT if concerned - Neuro exam - BP exam - Breast cancer screening age 40 - Family members - Derm - Ophthal - Genetic testing

Answer 46

``` BATANS Blooms Albrights TS Ataxia telangiectasia Neurofibromatosis - 1 & 2 Silver-Russell syndrome ```

Answer 47

increased epidermal melanin, giant melanosomes, higher number of melanocytes

Answer 48

- Unencapsulated dermal collection of small nerve fibres - loosely arranged spindle cells - scanty pale cytoplasm and elongated wavy nuclei, 'S' shaped nucleus. The spindle cells are fibroblasts, Schwann cells and perineural cells in collagenous stroma - Grenz zone - Varying amounts of mucin - Scattered mast cells - Stain S100

Answer 49

large hypertrophied nerves surrounded by spindle shaped fibroblasts and Schqann cells embedded in a myxoid matrix. Stroma may be more collagenous than myxoid, forming structures that resemble Meissner corpuscles. Look pretty similar to a neurofibroma.

Answer 50

- alternating cellular and myxoid areas - S100 positive - pleomorphic with wavy and hyperchromatic neucli - Increased mitotic activity - areas of bony or cartilaginous differentiation - It looks like a neurofibroma gone wrong

Answer 51

- Legius syndrome (see above) - Segmental NF1 - Partial uinilateral lentiginosis (freckling) - NF2 - don't have Lisch nodules, is very rare, more likely to get schwannomas - McCune-Albright: more precocious puberty, lesions are larger, have a linear or segmental distribution, do not cross the midline, and have an irregular border that may resemble the coast of Maine - Congenital melanocytic naevi

Answer 52

- The diagnostic criteria above - Genetic test: NF1 - FISH is available --> can identifying the underlying mutation in >95% - If segmental - can analyse the NF1 gene in melanocytes or Schwann cells

Answer 53

- Multidisciplinary team - Education regarding prognosis, complications, psychosocial - Genetic counseling - CALM - Lasers --> CALMs tend to recur - Surgical excision - Malignancy - Lifelong surveillance --> those at risk have plexiform neurofibromas, polyneuropathy secondary to multiple nerve root tumours, hx radiation therapy, germline NF1 microdeletion - PET assists with early detection - If symptomatic lesion --> biopsy - Other things: - Imatinib: inhibitor of c-Kit receptor on mast cells - Rapamycin (sirolimus) --> inhbits rapamycin and upstream PI3K/AKT signaling - Resources to give: Neurofibromatosis Network

Answer 54

- Autosomal dominant - 1 in 10 000 births - overall prevalence: 1/10000-30000

Answer 55

- Genetic mutation of TSC1 or TSC2 which results in disordered cellular proliferation, migration and differentiation - TSC1: encodes for hamartin which interacts with tuberin, functions to negatively regular mTOR signalling (this is where rapamycin works) - TSC2: on chromosome 16, encodes for tuberin --> it turns off Rheb in the mTOR pathway which inhibits cell growth and proliferation that result from mTOR signalling - Has a more severe phenotype - Is more common - If mosaic and gonadal --> results in generalised in offspring

Answer 56

``` Facial angiofibromas Hypopigmented macules Cephalic fibrous plaque Ungual fibromas Shagreen patch Molluscum pendulum CALM ```

Answer 57

Ocular - Retinal hamartoma (40%) - Most common type is a flat, translucent lesion (70%), followed by multinodular (55%) and transitional type lesion - Most ocular lesions don't lead to vision loss - Achromatic retinal patches - Retinal astrocytoma Skeletal - cystic areas of bone rarefaction Oral - Pitted enamel (90%) - Gingival fibromas (70%) - Most common type of intra-oral fibromas, but lesions can occur on buccal or labial mucosa and tongue Pulmonary - Lymphangioleiomyomatosis - Asymptomatic - 30-40% of women --> eostrogen suspected to be involved in stimulating growth of smooth muscle cells in the lung - CT: appear as cysts - usually attributed to TSC2 Renal - Multiple bilateral angiomyolipomas - Most of these are asymptomatic, especially in kids when <4 cm - Cysts - Children who develop severe renal cysts often have a contiguous gene syndrome --> TSC2 and PKD genes are lost in a single large chromosomal deletion - Carcinoma --> rare Endocrine - precocious puberty - hypothyroidism Neurologic - Infantile spasms occur in ~ 70% of infants, - last for several minutes, massive flexion or extension of limbs, trunk and head for <1-3 seconds - begin at about 3 months of age - different to seizures, EEG shows hypsarrhythmia - cortical tubers - Multiple subependymal nodules - On ventricular surface on MRI or CT in >80% of patients by 2 years - these calcify - Subependymal giant cell astrocytoma (SEGA) - 5-15% - develop during childhood - tend to enlarge over time, which may lead to neurologic symptoms - Seizures - 70-95% - Intellectual impairment >50% - TSC associated neuropsych disorders: autism, ADD, aggressive behaviours, psych conditions - Cortical dysplasia: cerebral white matter radial migration, glioneuronal harmatomas (90%) CVS - Myocardial rhabdonmyoma - >80%, can be detected pre-natally. Tend to involute within the first 3 years of life - Wolf Parkinson White

Answer 58

``` Definite: Require 2 major or one major plus 2 or more minor Possible: one major or 2 or more minor Definite genetic: TSC1 or TSC2 mutation Major: - Cutaneous: - >3 hypomelanotic macules, >5 mm in diameter - 3 or more facial angiofibromas, or one fibrous cephalic plaque - 2 or more ungual fibromas - 1 Shagreen patch - Extra-cutaneous - Multiple retinal hamartomas - Cortical dysplasias - Subependymal nodules - Subependymal giant cell astrocytoma - Cardiac rhabdomyoma - Lymphangioleiomyomatosis - Angiomyolipomas Minor - Cutaneous: confetti skin lesions - Extracutaneous - 3 or more dental enamel pits - 2 or more intraoral fibromas - Reetinal achromic patch - Multiple renal cysts - Non-renal hamartomas ```

Answer 59

- Facial angiofibromas (80%) - Centrofacial, as early as first 2 years of life - erythematous macules on cheeks and forehead, mature into pink to red or red-brown papules or papulonodules which may coalesce into plaques. Often dome-shaped and have a smooth, shiny surface - Bilateral and symmetric - Need at least 3 for dx

Answer 60

- Fibrous plaques (20%) - Larger variant of an angiofibroma on face or scalp - favour the forehead, are yellow-brown to pink-tan in colour - Grow slowly over time

Answer 61

- Hypomelanotic macules (90-100%), confetti - Not depigmented, like vitiligo, but are hypopigmented - Use Wood's lamp to detect these - Present at birth or within first few months - Small, polygonal or thumbprint shaped macules - Ash leaf spot: rounded at one end and tapered at the other, and can be 1-12 cm in size - Guttate or confetti: lots and lots, on extremities --> <5% of infants, but very specific - Require 3 or more, >5 mm in diameter for diagnosis - Can have associated poliosis

Answer 62

- Shagreen patch (40-50%) - These are actually leather, pig-skin like plaques which represent a collagenoma - Lumbosacral area, and occur around age 2 - skin coloured, hypo or hyperpigmented plaques that can be up to 10 cm in diameter, and have an uneven surface - Prominent, slightly depressed follicular openings giving rise to the pigskin like appearance - Also has been described as 'folliculocystic and collagen harmatoma' - comedones and keratin-containing cysts

Answer 63

- Ungual fibromas (30-60%) - Develop later in childhood and continue to form throughout adulthood - Can get periungual - from proximal or lateral nail fold and occur most commonly around the toenails - Subungual fibromas: originate under the nail plate, and have longitudinal red streaks with proximal narrowing - red comets, can result in longitudinal groove

Answer 64

- Molluscum pendulum - Large acrochordons and favour flexural areas - CALM - Around 30% - Usually <6 so no confusion with NF1

Answer 65

- Multiple endocrine neoplasia type 1: angiofibromas, gingival papules, confetti like hypomelanotic macules - Birt Hogg Dube: multiple facial angiofibromas, fibrofolliculomas, trichodiscoma - Acne vulgaris - Trichoepitheliomas --> less red in colour - Naevus depigmentosus - Idiopathic guttate hypomelanosis - Smooth muscle harmatoma - can present during infancy that may look like a Shagreen patch - accentuates with rubbing --> pseudo-Darier - contains follicular papules due to hyperplastic arrector pili muscles, and has associated hypertrichosis

Answer 66

- clinical trials: systemic therapy with mTOR inhibitors: sirolimus and everolimus has led to regression of SEGAS, control of recalcitrant seizures, reduction in renal angiomyolipomas and improved lung function - Newly diagnosed: - Neurodevelopmental evaluation - Brain MRI for tubers, migrational defects, subependymal nodules and SEGA - EEG if abnormal symptoms - Ophthal including dilated fundoscopy - ECG - TTE - Abdominal MRI: angiomyolipomas and renal cysts - Blood pressure and eGFR - High res CT in women of chest for lymphangioleiomyomatosis

Answer 67

- Neurodevelopmental evaluation 0-3, 3-6, 6-9, 12-16 and 18-25 years annually - Brain MRI every 1-3 years until age 25 to monitor for SEGA - EEG if seizure activity - Annual ophthal exam - ECG every 3-5 years in asymptomatic - TTE every 1-3 years in asymptomatic paediatric patients - Abdomianl MRI every 1-3 years - Annual BP and eGFR - High res CT every 5-10 years - Dental exam every 6 months - Annual derm exam - Genetic counselling and testing

Answer 68

- Derm and ophthal exam - Consider brain MRI, renal USS or TTE - Genetic testing consideration

Answer 69

- Electrosurgery - Dermabrasian - Ablative fractional or PDL - Topical rapamycin - 0.1-1% --> reduced erythema and flattening of angiofibromas typically seen within 3 months

Answer 70

Fibrofolliculoma, trichodiscoma angiofibroma and skin tags

Answer 71

1. Autosomal dominant 2. Gene MEN1 3. Mucocutaneous: 1. Multiple facial angiofibromas. Tend to be smaller and fewer compared to TS, more likely to arise on the upper lip. 2. Collagenomas 3. Lipomas 4. Rarely: gingival papules, confetti like hypopigmented macules, CALM, melanoma 4. Systemic: 1. Parathyroid 2. Pancreas 3. Pituitary

Answer 72

2. MEN, Sipple Syndrome 1. Autosomal dominant 2. Gene RET 3. Mucocutaneous 1. Pruritus 2. Lichen amyloidosis 3. Notalgia paraesthetica 4. Macular amyloidosis 4. Systemic 1. Thyroid 2. Adrenal - phaeochromocytoma 3. Parathyroid

Answer 73

1. Autosomal dominant 2. Gene RET 3. Mucocutaneous 1. Mucosal neuromas - especially eyelid margins, conjunctivate, lips, anterior tongue --> relatively specific for diagnosis 2. Increased nerve fibres in normal skin 3. Prominent, everted lips 4. Hyperpigmentation around mouth and overlying small joints of hands and feet 5. CALM 4. Extracutaneous 1. Thyroid 2. Adrenal - phaeochromocytoma 3. GI

Answer 74

- autosomal dominant with variable expressivity | - mostly Caucasian

Answer 75

- Tumour suppressor gene: PTEN - Also found in BRRS for which there is significant clinical overlap - PTEN downregulates PI3K/AKT/mTOR pathway that promotes cellular proliferation and survival - Hamartomas are typically from second hit somatic mutation --> loss of heterozygosity - Results in excessive mTOR signalling in affected tissue, particularly those with physiologic proliferation: epidermis, oral, GIT mucosa, thyroid, breast epithelium

Answer 76

- Birth to childhood: - Pigmented things: macules of genitalia, epidermal naevi, CALM - Benign growths of other things: lipomas, neuromas, vascular anomalies (tend to be multifocal, fast-flow with intramuscular involvement and associated ectopic fat), PTEN hamartoma (subcutaneous and intramuscular mass) - Adolescence to adulthood: - Things to be upset about: multiple facial papules, multiple oral papillomas (can be cobblestone), sclerotic fibromas, inverted follicular keratoses - Sclerotic fibromas: firm, dermal papules, that are uniform storiform pattern on histology - Insulin resistant things: achrochordons, acanthosis nigricans - Variable onset: - acral/palmoplantar keratoses - scrotal tongue - perioral pigmented macules (rare) - perhaps slightly increased risk of melanoma

Answer 77

- Birth: - Bones: macrocephaly, down-slanting palpebral fissures, frontal bossing, high arched palate, pectus excavatum, joint hyperextensibility, hand and foot abnormalities - GIT: hepatic vascular anomalies - CNS: seizures, developmental delay, hypotonia - Ocular: prominent corneal nerves, strabismus, amblyopia, retinal vascular anomalies - Muscular: lipid storage myopathy - Adolescence/adulthood: - Thyroid: goitre, cancers - Breast: fibrocystic, virginal hypertrophy, malignancies - GIT: cancer (rare) - GU: ovarian cysts, uterine leiomyomas, menstrual irregularities, testicular, renal cell cancer - Neuro: LDD: overgrowth of cerebellar ganglion - Variable: - CNS: meningiom - GIT: polyps - EyesL cataracts, myopia, angioid streaks

Answer 78

- they need 3 major criteria or 2 major and 3 minotr - Major: - Multiple mucocutaneous lesions: - Tricholemmomas - Acral keratoses >3 - Mucocutaneous neuromas - Oral papillomas - Pigmented macules on the glans penis - Macrocephaly - LDD - Cancers: - breast - endometrial - thyroid - GIT hamartoma - Minor - Vascular anomalies - Lipomas >3 or 1 testicular lipomatosis - Neuro: autism, mental retardation - Cancer: renal cell, colon, thyroid - Thyroid issues - Eosophageal glycogenic acanthosis

Answer 79

- Other genoderms: - Heck disease - MEN 2B - Goltz - Lipoid proteinosis - Darier: acral keratoses plus facial papules - Multiple facial tricholemmomas: - Angiofibromas - Trichoepitheliomas - Fibrofolliculomas (Birt Hogg Dube)

Answer 80

- Cancer surveillance - Yearly physical exam - Yearly thyroid USS - Scopes starting at age 35, repeat at least every 5 years - Women: annual mammogram and breast MRI - Consider: prophylactic mastectomies, random endometrial biopsies, renal USS from age 40 - Potential: sirolimus (downregulated mTOR pathway) - Facial papules: topical 5FU, oral roaccutane, curettage, laser ablation, surgical excision

Answer 81

``` Classic - 1 and 2 Hypermobile - 3 Vascular - 4 Kyphoscoliosis - 6 Arthrochalasia - 7a and 7b Dermatosparaxis - 7c ```

Answer 82

COL5a1 and a2 AD, Tenascin X AR

Answer 83

Tenascin-X, AR in 10%, but largely unknown, no genetic test

Answer 84

``` LTEACHINGS Lamellar Trichothiodystrophy CIE, conradi hunermann Haywell Nethertons, neutral lipid Gaucher Sjogren Larson, self improving Plus ectodermal dysplasias rarely ```

Answer 85

Acitretin 1 mg/kg/day

Answer 86

Short brittle hair due to low Sulfur content Polarising microscopy: tiger tail handing Light microscopy: trichoschisis- transverse fractures through the shaft, and trichorrhexis nodosa

Answer 87

1. Photosensitivity: poikiloderma, Dyspigmentation, no increased risk of skin cancers 2. Ichthyosis 1/3 have a colloidon membrane, resolves. Then follicular keratosis, eczema, itch 3. Brittle hair: tiger tail, trichoschisis, TN 4. Nail dystrophy, yellow 5. Neuro: intellectual disability, microcephalic, ataxia, spastic paralysis 6. Ortho: short stature, joint contractures, osteosclerosis 7. Decreased fertility - gonadal abnormalities REMEMBER PIBIDS

Answer 88

GJB3 and 4 Transient erythematous patches Hyperkeratosis

Answer 89

Skin: transient erythroderma, then get progressive huperkeratotic plaques, PPK, cheilitis, follicular occlusion triad, increased risk of infections and scc Eyes: keratitis, photophobia, blephaorotos, neovascularisation sndnscarring Neuro: dandy walker Hearing loss

Answer 90

Pili torti | Trichorrhexis nodosa

Answer 91

ATP7A, X linked Clinical: - Affected males has pili torti, severe psychomoter retardation, growth failure, seizures, other neuro issues - Pudgy face, cupid's bow upper lip, doughy skin, diffuse cutaneous hypopigmentation

Answer 92

Bjornstad - check for sensorineural hearing loss Menkes Bazex Dupre Christol, hypotrichosis with juvenile macular dystrophy, Laron syndrome, ectodermal dysplasias, mitochondrial disorders, urea cycle defects Acquired: retinoids, anorexia

Answer 93

Nethertons

Answer 94

- Young women - Localized area of uneven, fragile hairs - Hair is straighter and stiffer than normal - Light microscopy: shafts contain large, irregularly spaced bubbles that expand and thin the hair cortex - Fractures occur at larger bubbles - Cause: heat, hair dryer, hot iron on wet hair

Answer 95

- Congenital: - Intellectural disability and argininosuccinic aciduria or citrullinaemia - Tricho-hepato-enteric syndrome - Variants of acquired: - Proximal shaft: hair straightening - Distal: cumulative cuticular damage - Circumscribed: scalp, moustache, beard

Answer 96

- Young blonde haired girl with short hair that doesn't need a hair cut, very rarely can be boys and dark haired - Anagen hairs are pulled easily: ruffled proximal cuticle, absence of root sheath, bent matrix - Microscopy: abnormalities in the anchoring functions of the IRS --> loose attachment of the hair shaft to the anagen follicle - KRT75 mutation may be a thing - Improves with age - Ddx: TE, AA, trichotilomania, short anagen hair syndrome (kids: high terminal telogen hair count and short maximum hair length)