Photosensitive & skin malignancy

Question 1

XP

Answer 1

AR
XPA-G and XPV
Defects in DNA excision repair enzymes

XP A, C, V = account for 75%
XPA commonest in Japan (90% cases) = skin + neuro
XPB = skin + neuro  assoc cockayne, triothyodystrophy
XPC = commonest in USA (rare in Japan) = skin + NO neuro
XPV = 30% of all cases (USA, Europe, japan) = mild-severe skin + NO neuro

D same assoc B = skin + neuro = worst for neuro

2.3 per million live births in Western Europe, 1 in 20 000 in Japan, and 1 in 250 000 in the USA35
M=F

SON - SKIN OCULAR NEUTO
Clinical
Presents first few years of life
Infancy – sun sensivity and sunburn (erythema, inflammation, bullae)
Childhood/adolescence (in order of appearance)
- Pigmented macules (lentigines by 2yo), then achromic macules then teles in photodistribution
- Dry, scalp, atophic skin
- Narrowing of mouths and nares
- AKs, KA, 1000x inc BCC,SCC,MM

Eye (40%)

• Photophobia, conjunctivitis
• Tekes and pigmentation of lid and conjunctiva
• Ectropion, corneal vasculizarization and opacification
• Lid skin cacncers

Neurological (20% cases – most XPA and XPD)

• Progressive neuro degeneration, hyporeflexia, spasticity, ataxia
• Mental retardation
• Sensorineural deafness+/- microcephaly

Other malignancy
- ~10-20x increase internal malignancies - tumors of the brain, lung, oral cavity, gastrointestinal tract, kidney, and hematopoietic system.

Prognosis: Early death can occur from skin malignancy if not identified early
Neuro degen is progressive

Ix
DNA analysis
UDS = unscheduled DNA synthesis (on cultured amniotic fluid cells)

Mx
Education – inheritance, risk transmission, complications/red flags, MDT approach, no cure but maximise life

Support Group + psych
Genetics

Derm

• FSE Q3/12 + photos
• Prevention - strict photoprotection, change from day to night shift (physical blocker, UV graded clothing, hat, sunglasses).
• Prevention - retinoids
• Vit D supp/monitoring
• Field rx efudix, imiquimod, 5FU, currentage, excision

Opthal – regular screening/rx cancer, soft contact lens, corneal transplant

Neuro/paeds – height, weight, development. Test reflex + audio testing.

DDX = EPP, CEP, Bloom, Cockayne, Rothmund Thomson, Hartnup

Question 2

Gorlins

Answer 2

AD
PTCH1 (PATCHED) = tumour suppressor gene encoding sonic hedgehog receptor protein (smoothened)

1:60,000
M=F

Clinical criteria
Bcc COP Family MAJOR
BCC >2 any age, >1 if under 20, >10 lifetime
Calcification falx cerebri or lamella calcification
Odontogenic keratocysts on histo
Palmoplantar pits
Family history

MINOR

Clinical summary
Skin, Bone, Eyes, Intellect, malignancy
BCC COOP MM
Bcc, calcification, ofotogenic, ocular, pits, malignancy, mental

Skin

• Multiple BCC (usually after puberty) – sun exposed and sun protected sites (nodular face, superficial torso – like normal pop)
• Palmoplantar puts
• Epidermoid cysts
• Milia

MSK/Bone
-	Odontogenic keratocyts (usually in molar and premolar areas)
-	Frontal bossing, bifid rubs
-	Vertebral fusion, kyphoscoliosis
CNS
-	Calcification falx cerebri
-	Agenesis corpus callosum
-	Mental retardation
Eyes
-	Hypertelorism
-	Congenital blindness, cataracts
-	Colobomas, strabismus
Genitorurinary                                                                                                
-	Ovarian fibromas, fibrosarcoma
Other malignancy
-	medulloblastoma
2M or 1M and 2m
Prognosis = good if malignancy caught early

Ix
Prenatal DNA mutation analysis
Skin biopsy
Skeletal survey – skull, maxilla, mandible, rubs, vertebrae

Rx
Education – inheritance, risk transmission, complications/red flags, MDT approach, no cure but maximise life

Support Group + psych
Genetics

Prevention – photoprotection, avoid radiotherapy/XRAYs, oral retinoids, Vit D/Ca

Refer dentist
Derm – Q3/12 skin checks, multiple methods of excision including MOHs; VISMODEGIB
Opthal
Neuro

DDX Bazex, unilateral linear nevoid BCC, melanocytic nevi, Rombo syndrome, XP

Question 3

Muir Torre

Answer 3

AD (most cases familial, occasional sporadic)

Defect in MMR DNA mismatch repair genes MLH1 on 3p (<10%)and MSH2 on 2p (most common)
 v rare MSH6 (less commonly assoc w colon cancer but higher extracolonic malignancies esp endometrial ca which has earlier onset) and PMS2 gene

M=F, several hundred cases reported.
50s (but early as 20s); commoner in caucasians

Tumours in 50s, typically Caucasian, M=F, usually fx hx

Skin
20-30s (22-32% before internal ca, 6-12% at same time, 56-59% after internal malignancy)
• Multiple sebaceous tumours  hyperplasia, epitheliomas (31-86%, adenomas (25-68% commonest), carcinomas (66-100%). These usually not aggressive.
 Sometimes ophthalmic sebaceous tumours are first sign
• BCC with sebaceous differentiation
• KAs (20%) – multiple, can be sun protected sites, younger age. SCC also described but not common.

Internal malignancy
 50% have >/=2 visceral carcinomas. 10% >4 primary tumours
 most commonly appears before skin lesions
• Adenoca colon (commonest)
• GIT, GU, lung, breast, stomach, small bowel, liver, kidney, pancreas, haem malignancies described.

Note >50% have multiple sebaceous tumours, primary int caexinomas (colorectal)

Assoc – immunosuppression following renal transplant may exacerbate tumours (switch from tacro to sirolimus may help)

Malignancies usually low grade with good prognosis (better than non MT pts with same)
Can have normal life span (if close surveillance and early detection of maligfnancy)

Ix
DNA anlysis pre natal dx
Skin biopsy
Endoscopy/colonscopy – variable (1-2yr high risk; otherwise Q3 yrs)
Genetic counselling
+ Refer family members to geneticis and early bowel screening

Management
MDT
Genetics (+ family)
Derm FSE + EOL with clear histological margins
Gastroenterology – scopes
Consider annual CXR, urine cytology
Female – annual pap smear + CEA + mammogram annually + consider endometrial bx Q3-5yr
Age appropriate malignancy screen + according to sx

Use of isotretinoin as prevention reported.

DDX
Familial adenomatous polyposis = colon ca, colon polyps. Herpatoblastoma, thyrpid, pancreatic adrenal, bile duct tumours, osteomas, unerupted or extra teeth, congenital hypertrophy retinoid pigment, desmoid tumours, venign skin lesions, erpidermoid cyst, fibromas.
Cowden syndrome
Gardner syndrome – higher risk colon ca. Develop sebaceous cysts, epidermoid cysts, fibromas, desmoid tumours, soteomas (not seen in MT)
Overlap with Turcot syndrome and MT = Seb ca, colon ca, astrocytoma

Question 4

Bloom syndrome

Answer 4

AR
BLM gene encose RecQLD3 = DNA helicase normally assists with DNA repair.
Slight M > F
Commoner – Ashkenzai Jews from Eastern Europe
Approx 250 patients

First few months of life
Skin
-Photodistributed erythema, teles +/- bullae     (nose, cheeks, ears, forearms/hands)
-Cheilitis
-CALM
*Skin changes decrease with age
Facies/habitus
-Short stature, long narrow face with prominent nose, small mandible and malar hypoplasia

High pitched voice

Immuno
-Decreased IgA, M +/- IgG  recurrent resp/gastro infections

Fertility

• Males, Infertile, hypogonadism
• Females reduced fertility

Neoplasia (20%)

• Acute leukemia, lymphoma
• GI adenoca

PROGNOSIS
Premature death in 20-30s can occur due to malignancy bt not in all patients.
High risk complications from infections

Ix
DNA analysis
Chromosome analysis
Immunoglobulin

MANAGEMENT
Education
MDT
-Derm – diagnosis and photoprotection
-Immunology, ID, haem/onc, endocrine
Genetics
Support groups/ Psych

DDx
Helicase family mutations also in – Weners, XP (B, D), Rothmund Thompson
EPP
Lupus

Question 5

Rothmund Thompson

Answer 5

AR
RecQL4 helicase gene
F>M
300 cases

CLINICAL
RT = PAM TANS by the C
Poikildermatous changes, acral keratoses, Malignancy (SCC, osteosarcoma)
Teeth, alopecia, nails, Skeletal (short stature, hypoplastic radius)
Cataracts

Skin (UVA sensitive)
o 3-6 months old Erythema, oedema, vesicles face
o Rapidly replaced by red/brown reticulate patches
o Assoc poikilodermatous changes – atrophy, hypopigmentation, teles
 can be on Face/extensors of extremities but also photoprotected sites like buttocks
o After puberty  verrucous mostly acral keratosis  may develop into SCC
Hair
Alopecia – scalp, brows, lashes
Nail dystrophy/hypoplasia (25%)
Teeth – dysplasia

Eyes – cataracts 50% by 3-7yo

MSK
Short stature,small hands/feet, absent/hypoplastic thumbs
Variable skeletal anomalies - osteoporosos
Osteosarcoma (rare(

25% hypogonadism (may be assoc with saddle nose midface hypoplasia)

Malignancy (rare)
Repots only – SCC, fibrosarcoma, osteosarcoma

Ix
DNA analysis
XRAY long bones

Mx
Derm – diagnosis + FSE, photoprotection
Opthal – annual screen (cataracts)
Ortho, dentist, endo/haem as needed.

DDX
DDx – DNA heliace defects in RT,Bloom, Weners, XP
Cockayne
Wener, kindler

Question 6

Cockayne Syndrome

Answer 6

AR
DNA repair genes  hypersensitive to UVR + progressive neurodegeneration
Gp A ERCC8
Gp B ERCC6
1.	1 per 360 000 births

CS type I: 80% of patients; onset at birth to 2 years of age, progressive; life expectancy: second to third decades

CS type II: symptoms at birth, life span = 6–7 years

CS type III: late onset, normal growth and development

CLINICAL
Presents birth-2yo; sometimes later in teens

Skin
-	Photosensitive – scale/erythema butterfuly distribution on face  may resolve with hyperpigmentation, atrophy
-	Aged appearance and sunken eyes due to subcut loss on face
Alopecia
Nail clubbing
Craniofacial
-	Dwarf like “Mickey mouse”
-	 cachetic, microcephaly, disproportontately long limbs, joint contracture, large cold hands and feet
CNS
-	Progressive diffuse demyelination fo CNS and peripheral nerves  mental retardation, intracranial calcifications
-	Sensorineural deafness
Eyes
-	Salt and pepper retinal pigment
-	Mitotic pupils hard to dilate
-	Cataracts, optic atophy
Dental caries
Hypogonadism
No increase in malignancies in “pure” CS

Ix
Amniocentesis/amniotic fluid culture – deficiency RNA synthesis + inc cell death after exposure to UVR
DNA analysus
Brain CT – calcifications, cortical atrophy
Hearing test