Familial cancer syndromes Flashcards
Name and outline common features of the RecQ helicase gene mutation genodermatoses
Werner’s syndrome RecQL2
Bloom’s syndrome RecQL3
Rothmund-Thomson syndrome RecQL4
5 features (2,3,4,5) Autosomal recessive Abnormal growth-short stature Premature ageing Photosensitivity Site specific cancers
All need;
Strict sun protection + regular skin checks
speacilaist referrals for benign and malig changes
ongoing cancer surveillence
genetic counselling
Camouflage or cosmetic treatments for skin changes
What is Wiskott-Aldrich syndrome?
Mutation of WASp gene X-linked recessive - affects males only Eczema Thrombocytopenia Immunodeficiency with low IgM
Often bruising, bloody diarrhoea and recurrent infections esp sinusitis, URTI and LRTI - cause petechiae and bruising of skin and mucosae
Get splenomegally, lymphoma and leukemia
25% get NHL in 20s
Which syndromes are associated with epidermal cysts?
EGG-CPK Gardner's Gorlin's Cowden's Pachyonychia congenita type 2 KID syndrome
What is Bannayan-Riley-Ruvalcalba syndrome?
What is the gene and inheritence?
AD PTEN mutation (in 60%) with many same features as Cowden’s
Macrocephaly, penile lentigines and hamartomatous tumours (lipomas, haemangiomas, GI hamartomatous polyps)
Sometimes skin haemangiomas or AV malformations
Penile lentigines are commonest feature (in males) and develop in mid-childhood
Risk of cancer (need to monitor); thyroid, breast, bowel
What are the features of Bazex syndrome?
Bazex-Dupre-Christol
Follicular atrophoderma-BCC syndrome
BAZEX Mili Pili dark face lumpy uglies
BCCs - esp on face
Atrophoderma - follicular, of extremeties
Zero sweat - hypohidrosis above neck
Empty follicles - scalp hypotrichosis in males
X-linked dominant (males + females affected)
Also; Milia Pili torti, trichorrhexis nodosa Genital trichoepitheliomas Facial hyperpigmentation
What is Tuberous sclerosis complex? What is the triad? What are genes and inheritance? What are the dermatologic features? What are the complications?
Common AD multiple hamartoma syndrome - skin, brain, eyes, kidney, heart classical triad; - Angiofibromas - Learning difficulties (60%) - Epilepsy Genes TSC1 gene codes Hamartin TSC2 gene codes Tuberin - more commonly affected. 2 thirds new mutations Major derm criteria; - Facial angiofibromas or forehad plaque - 3 or more Ash leaf/ hypopigmented macules - Shagreen patch - collagen naevus - Periungual fibromas (non traumatic)= Koenen's Other derm features; - Confetti hypopigmentation on legs - minor criterion - Neck and axillary fibromas - CALMs - Poliosis complications; - visceral hamartomas - oropharyngeal fibromas - CNS tumours esp gliomas - diffuse cutaneous reticulohstiocytosis - cardiac, renal, eye, lung hamartomas - pituitary dysfunction, thyroid disease
What are the diagnostic criteria of Neurofibromatosis type 1?
What is the gene and inheritance?
AD, NF1 gene on Chr 17
encodes Neurofibromin
Need 2 out of 7 features;
Six or more café-au-lait spots or hyperpigmented macules >5 mm in diameter in prepubertal children and 15 mm postpubertal
Axillary or inguinal freckles
Two or more typical neurofibromas or one plexiform neurofibroma
Optic nerve glioma
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
First-degree relative (eg, mother, father, sister, brother) with NF1
What are non-derm features of NF1?
What are complications of NF1?
Learning difficulties 25% Neurological problems 40% Headache Epilepsy Endo – precocious puberty, acromegaly, Addisons, hyperparathyroidism, phaeochromocytoma, gynaecomastia Pulmonary HTN Renovascular HTN osteomalacia due to renal disease GI obstruction or haemorrhage Congenital heart defects
Complications
Malignant peripheral nerve sheath tumour
Sarcomatous change in a neurofibroma - esp visceral
CNS tumours - optic nerve glioma most common solitary intracranial tumour
Melanoma
Wilms tumours
Rhabdomyosarcoma
Leukaemias
NF1 children with JXGs have >20x increased risk for CML (JMML)
Retinoblastoma
Blindness from optic glioma or other CNS/retinal tumour
Phaeochromocytoma
CVS, endo, renal, resp, bone complications
What is Gardner’s syndrome?
What is inheritance?
What are complications?
Variant of FAP - AD w/ variable expression
APC gene
The Chirpy (CHRPE) gardener LLOPED the Mulberry Tree
cancers - MCDonald Likes PAT
Congenital Hypertrophy of Retinal Pigment Epithelium
Lipomas - subcut and visceral
Leiomyomas - bowel polyps and retroperitoneal
Osteomas - small, in facial bones esp, in 80%
Pilomatrixomas (and Polyposis), fibromas, neurofibromas
Epidermoid cysts - common, early, face, scalp, limbs
Desmoid tumours -aggressive, at trauma sites
Medulloblastomas (a malignant brain tumour)
Teeth – supernumerary; odontomas; multiple caries
Cancers;
Medulloblastoma
Colorectal carcinoma
Dudodenal
Liver (hepatoblastoma)
Pancreas
Adrenal
Thyroid (papillary)
NB;
If pt presents with multiple epidermoid cysts (esp on face) ask about fam Hx and do full skin exam. Consider arranging imaging of skull bones for osteomas, colonoscopy and fundoscopic exam of retina
What is Muir-Torre syndrome?
What are genes and inheritance?
What are complications?
Rare subtype of Lynch syndrome (HNPCC) AD w/ variable expression Loss of function mutation of a tumour suppressor gene for DNA mismatch repair protein due to microsatellite instability. 4 genes in order of freq; MSH2 - most commonly mutated MLH1, PMS2, MSH6 Sebaceous skin tumours - occur later than cancers - sebaceous adenoma (most common) - sebaceous epithelioma/ sebaceoma - sebaceous carcinoma (usually off face) - sebaceous keratoacanthomas (less common) Malignancy risk - MUIR T Marrow - Haematological 5% Uterine and ovarian Ileum - Colon + other GI cancers (in 50%. At young age) Renal tract cancers (occur in 25%) Tits - Breast 5%
What is Cowden’s syndrome?
What are genes and inheritance?
What are complications and management?
Rare AD multiple hamartoma syndrome
PTEN (on Chr 10) gene mutation most often
complex clinical criteria which if met should trigger referral for gene testing
Important skin features - CAT PP;
Cowdens fibroma - any site
Acral punctate PPK (at least 6)
Trichilemmomas on face around mouth, eyes and chin (at least 3)
Periorifical papules (cobblestone, lichenoid) around mouth and eyes
Papilomatosis + fibromas of mucosa
+/- other skin features - CAVES;
CALMs
Acral keratoses on dorsal hands/wrists resembling acrokeratosis verruciformis
Vitiligo
Epidermoid cysts
Storiform collagenomas
Non derm features + complications;
Craniomegally (70%), sometimes adenoid facies
Fibrocystic breast changes in women + Ca breast
Goitre, thyroid adenoma or follicular thyroid carcinoma
Uterine/endometrial adenocarcinoma
sometimes; GI hamartomatous polyps, learning difficulties
Cancers - TMBUG -thyroid, Melanoma, breast, uterine, GU
Mx early malignancy screening - FSE and referrals monitor thyroid no oestrogens for women as Ca risk genetic counselling cosmetic skin Rx - surgery, laser etc
What are the features of Birt-Hogg-Dube syndrome?
What is the gene and inheritance?
rare AD mutation FLCN - Folliculin gene FAT hog Face Book TRAMP (or Fucked By TRAMP) multiple; - Fibrofolliculomas (folliculin gene) - Achrocordons (morphology of F or T) - Trichodiscomas sometimes; Flecked choroidretinopathy - F Bowel polyps - B medullary Thyroid carcinoma - T Renal cell carcinoma – R - Is an RCC syndrome Angiofibromas - A cutaneous Mucinosis - M Pneumothorax due to lung cysts - P
What is Dyskeratosis Congenita?
What is the triad and other features?
Very rare ectodermal dysplasia and immune deficicency syndrome.
Dysko RON
Usually fatal in 20s or 30s
several genes involved in maintaining telomere length during cell division esp Dyskerin gene, DKC1
XLR most often - affects males mainly
rare AD and AR types are milder
Triad - ‘RON is sweaty not hairy’ and is ‘A POM’
Reticulated skin hyperpigmentation (like poikiloderma) of neck, face, trunk and upper thighs
Oral leukoplakia (premalignant) + malaligned teeth, caries
Nail dystrophy + loss and pterygium
Also; Palmoplantar - acrocyanosis - hyperkeratosis - friction blisters Generalised - Hyperhidrosis (sweaty) - Hypotrichosis + alopecia; scalp, brows, lashes (not hairy) Ectropion, blepharitis and lacrimal problems mental impairment vulval and anal leukoplakia Cancers - A POM; Aplastic anaemia Pancreatic cancer Oropharyngeal SCC arising from leukoplakia Myelodysplasia, AML, Hodgkins lymphoma
What is Gorlin's syndrome? What is the gene and inheritance? what are features and diagnostic criteria? What are the complications? What is the management?
AD mutation in patched gene PTCH1
common 1 in 55,000
Skin
- BCCs
- Milia
- Acrochordons
- Palmoplantar pits
- Epidermoid cysts
Face - frontal bossing, hypertelorism, broad nasal root
Cranial - macrocephaly, calcification of falx cerebri
Bones - odonogenic jaw keratocysts, bifid ribs, spina bifida occulta or other rib, spinal or digital bony defects
Other - male hypogonadism, female bicornuate uterus, lymphomesenteric cysts, neuro and occular problems
Neoplasia (other than BCC)
- Ovarian and cardiac fibromas
- Medulloblastoma (childhood brain malignancy)
- Rhabdomyosarcoma
2 major or 1 major and 2 minor criteria.
Major criteria - BOPFC
• 3 or more BCCs at any age or one BCC less than 20 years or >10 basal cell naevi
• Odontogenic keratocyst or a polyostotic bone cyst
• 3 or more Palmar / plantar pits
• Family history of Gorlins
• Calcification of the falx cerebri or other ectopic calcification
Minor criteria - MMBLOC
• Macrocephaly with frontal bossing
• Medulloblastoma in childhood
• Bifid, fused, splayed, or missing rib, or bifid, wedged, or fused vertebra
• Lymphomesenteric cyst in abdo or pleural cyst
• Ovarian or cardiac fibroma
• Congenital malformation: cleft lip and/or palate, polydactyly, congenital eye defect such as cataract, microphthalmos or coloboma
Mx
- genetic counselling
- referals - dentist, ophth, ortho, cardiac, neuro, oncology
- sun protection
- EOL face, C+C, cryo, PDT, aldara cream, efudix, isotretinoin, Vismodegib, No XRT
What is Rothmund-Thomson syndrome?
Very rare AR condition
mutation of RecQL4 helicase gene
poikiodermatous photosensitive cancer genodermatosis
Features;
Poikilodermatous (radiation dermatitis-like) rash of cheeks, butocks, hands and feet and later arms and legs
photosensitivity, premature aging
hyoplasia of thumbs, forearms or tibias
short stature, bird-like facies, saddle nose, small head
juvenile bilateral cataracts
small dystrophic nails
hypotrichosis and sparse eyelshes and brows
Osteosarcoma, NMSC and other tumours
- refer to ophthal and ortho
- do annual FSE
What are the diagnostic criteria of tuberous sclerosis complex?
Need 2 majors or 1 major and 2 minors for definitive diagnosis
1 major or 2 minors for possible TSC
Can also get definite genetic diagnosis by identification of a pathogenic mutation in TSC1 or 2
Major features – PASH McCLASS
- 2 or more Periungual (or ungual) fibromas
- 3 or more facial Angiofibromas or forehead plaque
- Shagreen patch
- 3 or more Hypomelanotic macules (Ash-leaf macules), at least 5mm diameter
- Multiple retinal hamartomas
- Cortical dysplasia (tubers or white matter migration lines)
- Cardiac rhabdomyoma
- Lymphangioleiomatosis (LAM)(lung)
- Angiomyolipoma (usually renal)
- Subependymal nodule
- Subependymal giant cell astrocytoma
Minor features – PINCER
- Polycystic kidneys - P
- 2 or more Intraoral (gingival) fibromas - I
- Non-renal hamartoma - N
- ‘Confetti’ skin lesions - C
- dental Enamel pits (multiple, randomly distributed, 3 or more) - E
- Retinal achromic patch - R
In what order do the cutaneous signs of TSC arise?
AASK
Ash-leaf macules (birth or present by 3 months)
- 0.2% of normal neonates have hypopigmentd lesions
Angiofibromas face (From 2yrs and by adolescence in 80%)
Shargreen patch (from 2 yrs of age)
Koenen’s tumour (from 4yrs and continue to develop into adulthood)
What are the features of Peutz-Jagher’s syndrome?
What is the gene and inheritance?
What are the complications?
AD
STK11/LKB1 gene (tumour suppressor)
40% new mutations
mucocutaneous lentiignes from early childhood
- oral always involved
- can be palms, soles, nails, eyes, nose, perianal
hamartomatous polyps esp small bowel
Complications PR bleeding, intussusception, obstruction Cancers - PEUTZ Pancreas Endometrium, cervix, ovary/testes Uterine Tits (breast) Z - Z(s)igmoid - Bowel Ca
Need genetic counselling and early cancer screening
No derm Rx except cosmetic
What are the features of the Multiple Endocrine neoplasia syndromes?
MEN 1; mutation in MEN1 gene
Pts get benign adenomas causing endocrine problems
PPP+CA
Pituitary adenoma
Parathyroid hyperplasia (causes high calcium)
Pancreatic islet tumours (gastrinomas, insulinomas, glucagonomas - peptic ulcers, blood sugar problems, can get necrolytic migratory erythema)
Collagenomas
Angiofibromas – multiple facial (DD for TSC)
MEN 2 syndrome - has 2 syndromes; A and B
Few or no mucocutaneous features
They have endocrine cancers not adenomas
Medullary thyroid carcinoma
Phaeochromocytoma
Plus;
MEN2A - parathyroid adenoma (usuallly no skin features but 1/3 of pts egt macular or lichen amyloidosis of upper back presenting before age 10)
MEN2B - marfanoid habitus, mucosal neuromas
What is sclerotylosis/ Huriez syndrome?
Some People Hurry
diffuse Scleroatrophy of the hands mild PPK Hypoplastic nail changes
Increased risk of skin SCC and bowel cancer Scleroatrophy is like sclerodactyly but no Raynauds
Nail changes include prominent lunulae, elongated cuticles, longitudinal and transverse ridging, increased longitudinal curvature and V shaped notches
Acitretin may help
What is epidermodysplasia verruciformis?
3 Vs;
Verruca plana - extensive
Violaceous plaques
Pityriasis Versicolor - like scaly, depigmented lesions
Beta genus HPV infection- doesn’t affect normal immunocompetent people (HPV 5 and 8)
50% develop SCC in sun exposed sites but are of low metastatic potential
What are the Amsterdam criteria for HNPCC?
All 3 of;
- 3 or more relatives with an HNPCC-associated cancer (ie, colorectal, cancer of the endometrium, small bowel, ureter, or renal pelvis)
- Cancer affecting at least 2 successive generations
- One person with cancer is a first-degree relative of the other 2, at least 1 case of colorectal cancer younger than age 50 years, a diagnosis of familial adenomatous polyposis has been excluded, tumors are verified by histologic examination
What benign and malignant features do Gorlins and Gardners sundromes have in common?
Epidermoid cysts
Meduloblastomas in childhood
What is Xeroderma pigmentosum?
Rare AR genetic disease; XP gene
Mutation of nucleotide excision repair genes (except variant type; XPV)
8 subtypes (complementation groups); XP A-G + XP variant type (XPV)
Pts are unable to repair UV (A or B) induced DNA damage
Infants get severe sunburn with erythema, pain and bullae
Pigmented macules, achromic macules + telys + angiomas in photodistributed areas
Usually have solar lentigines by age 2
Dry (xerotic = Xeroderma), scaly, atrophic skin
narrowing of mouth and nares; May get ectropion and slow healing ulcers
Median age of onset of cancers is 8 years
AKs, KAs, SCC, BCC, melanoma – 1000x increased risk for all major skin cancers
SCC on tongue and oral mucosa esp anterior
photophobia, conjunctivitis early on; Later ulceration and symblepharon of conjunctivae due to ectropion, pigmented macules on conjunctiva, pterygium, corneal opacities, keratitis, epitheliomas of lids/conjunctiva/cornea
learning difficulties in some types
10-20 x increased risk of internal malignancies – brain , lung, GIT, kidney, haematological and oral mucosa
some types alos have Cockayne sundrome
2 thirds die before age 20
Some mild cases survive to middle age with treatment
