Heritable disease and syndromes Flashcards
What is Stewart- Treves syndrome?
Angiosarcoma in setting of long-standing lymphedema (post lymph node dissection)
What are symptoms of glucagon-secreting tumours?
necrolytic migratory erythema (NME) diabetes mellitus Hypoaminoacidemia Cheilosis Normochromic, normocytic anemia Venous thrombosis Weight loss Neuropsychiatric features.
What is Doege-Potter syndrome?
Paraneoplastic syndrome associated with solitary fibrous tumour Hypoglycemia from expression of IGF-1 (insulin-like growth factor)
Features of tuberous sclerosis
Central nervous system: SEGA, cortical tubers (epilepsy, learning difficulties, behavioral problems, and autism) Renal: angiomyolipomas (hemorrhage or by compression), renal cysts and renal-cell carcinomas Pulmonary: lymphangioleiomyomatosis Skin: shagreen patch, melanotic macules, ash-leaf patch, subungual fibroma, facial angiofibromas, connective tissue nevi, adenoma sebaceum Other: Sugar tumours of pancreas, lung and uterus; cardiac rhabdomyomas; retinal hamartomas
MEN1
AD, MEN1 11q13, menin Manifestations: Parathyroid hyperplasia Pancreatic neuroendocrine tumours Pituitary adenoma Duodenal gastrinoma Carcinoid tumours of thyroid Adrenocortical adenoma and lipomas
MEN2A
AD, RET 10q21, exons 10, 11, 13-15 Manifestations: -medullary thyroid carcinoma - 100% -parathyroid hyperplasia - 10-35% -pheochromocytoma - 50%
Carney Complex
AD, PRKAR1A protein kinase A type 1 alpha regulatory subunit, 17q23 (CCN1) or 2q16 (CCN2) Manifestations: Pituitary adenoma Cardiac myxoma Myxoid skin lesion Blue nevi Lentigines Pigmented schwannoma Sertoli cell tumour
NF1
AD, 17q11.2 neurofibromin 50% de novo mutation Manifestations: Neurofibromatosis (plexiform) Café au lait spots Inguinal/axillary freckling Optic nerve glioma Pheochromocytoma Duodenal somatostatinoma Lisch nodules Choroidal nevi Sarcoma Vascular dysplasia Wilms tumour Leukemia
Polyglandular autoimmune syndrome (ASP1)
Clin: Present as younger children as candidiasis, then later hypoparathyroidism and then adrenal insufficiency as adult 21q22, AIRE autoimmune regulator gene AIRE is a transcription factor expressed in thymus Stimulates production of peripheral antigens for the selection of self-reactive T cells for clonal destruction Manifestations: Autoimmune hypoparathyroidism/polyendocrinopathy Primary adrenal insufficiency Mucocutaneous candidiasis Ectodermal dystophy (nails, skin and dental enamel)
McCune-Albright
Manifestations: Hyperthyroidism Precocious puberty Cafe au lait – Coast of Maine Polyostotic fibrous dysplasia Fractures/bowing limbs Diffuse sclerosis of skull base
von Hippel Lindau
AD, VHL 3q26.25 Manifestations: Pheochromocytoma Adrenocortical carcinoma Vascular malformations CNS hemangioblastoma Renal cell carcinoma and renal cysts Endolymphatic sac tumour of ear
Manifestations of VHL
RCC Hamangioblastoma Pheochromocytoma Paraganglioma Pancreatic endocrine neoplasm Endolymphatic sac tumour
Birt-Hogg-Dube
AD, FLCN codes for folliculin Hair follicle hamartomas (fibrofolliculomas, acrocordons) Multiple oncocytomas or chromophobe carcinomas, or oncocytosis Spontaneous pneumothorax Increased risk of CRC
Manifestations of lead poisoning
Brain: HA, memory loss; peds: encephalopathy, MR Gingiva: Burton’s lead lines Blood: anemia, red cell basophilic stippling Peripheral nerves: demyelination Kidny: chronic tubulointerstitial disease GI: abdominal pain Bones: peds: radiodense deposits
Mechanisms of lead toxicity
Interference with calcium homeostasis Interferes with cartilage and bone remodelling, esp epiphysis Increased chondorgenesis anddelaying minerlaisation Inhibit heme synthesis enzymes: delta-aminolevulinic acid dehydratase and ferrochetelase – rise in protoporphyrin levels
Familial pitiuitary adenoma
MEN1 (menin, MEN1) MEN1-like (Kip1, CDKN1B) McCune-Albright (Gs-alpha, GNAS) Carney complex (PRKAR1A) Familial Isolated Pituitary Adenoma (AIP)
CK+/Vimentin+
RCC, clear cell type Endometrium Mesothelioma Salivary gland Thyroid Sweat gland Spindle cell carcinoma of any site
CK+/Vim-
RCC, chromophobe type Endocervix (adenocarcinoma) Lung carcinoma Breast Ovary Prostate Colorectum HCC
CK +/ EMA-
HCC (Cam5.2+, AE1/AE3–, CK903–) Adrenocortical neoplasms (frequently negative for all CKs) Most neuroendocrine neoplasms Embryonal carcinoma, yolk sac tumor Thyroid
CK-/EMA+
Meningioma Perineurioma Plasma cell neoplasms Anaplastic large cell lymphoma Popcorn or lymphocyte predominant (LP) cells [formerly L&H cells] in Hodgkin lymphoma RCC (sometimes)
CK+ non-epithelial tumours
Epithelioid sarcoma Synovial sarcoma Desmoplastic small round cell tumour, angiosarcoma
Pediatric fibrous proliferations
Fibrous hamartoma of infancy – solitary poorly circ proliferation of loosely shaped spindle cells in organoid nodules in fatty tissue Infantile digital fibromatosis – small round intracytoplasmic inclusions (size of lymphocyte, actin) Infantile myofibromatosis – small bundles of spindled cells, like sm. Mm. Juvenile hyaline fibromatosis – AR, cutaneous nodules, gingival hypertophy and flexure contractures, keloidal collagen Fibromatosis colli – rapidly gorwing mass in 2-4th week of life, diffuse scar iwthin skel m. Calcifying aponeuroic fibroma – ill-defined and painless masses on hands and feet of children between 10-15 y with primitive mesenchymal cells resembling fibromatosis or FS around Ca2+
Seminoma IHC
(+) for Oct3/4 (nuclear), D2-40, c-kit & PLAP (-) for cytokeratin (may be focal or weak), CD30(BerH2), & α-fetoprotein
testicular tumours are more likely to be bilateral in which: seminomatous or non-seminiomatous?
non-seminomatous tumours
Testis TNM
pTis: Intratubular germ cell neoplasia (carcinoma in situ) pT1: Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade tunica albuginea but not tunica vaginalis pT2: Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis pT3: Tumor invades the spermatic cord with or without vascular/lymphatic invasion pT4: Tumor invades the scrotum with or without vascular/lymphatic invasion
IHC Chromagens? Red and brown?
Brown - Diaminobenzidine Pink - aminoethylcarbazole (fast red)
Paratesticular lesions
Adenomatoid tumour Fibrous psuedotumour
Hereditary papillary renal cell carcinoma syndrome
AD multple bilateral papillary RCC, type 1 Activating mutation in c-MET protooncogene (7q31)
Hereditary leiomyomamatosis and renal cell carcinoma syndrome
AD Manifest: leiomyomas of skin and uterus, occ LMS of uterus, RCC Inactivating mutation in fumarate hydratase (FH) (1q42.3-q43) RCCs are aggressive (PRCC type 2 or collecting duc RCC) - usually solitary and unilateral
Hyperparathyroidism-jjaw tumour syndrome
Mutation in HRPT2, parafibromin 1q21-32 Manifest: hyperparathryroidism and parathyroid tumours, fibroosseous tumours of jaw; renal cysts, hamartomas, RCC, Wilms tumour
Familial pediatric renal tumour syndromes
WAGR Denys-Drash Beckwith-Weidemann syndrome Familial nephroblastoma Trisomy 18 Perlman syndrome Bloom syndrome Frasier syndrome Klippel-Trenaunay syndrome
WAGR
- Wilms tumour, aniridia, genitourinary malformation, mental retardation
Denys-Drash syndrome
Wilms tumour mesangial sclerosis psuedohermaprhoditism
Beckwith-Wiedemann syndrome
Wilms tumour, hemihyerptrophy, macorglossia, omphalocele, visceromegaly
Classification of fibromatosis
Superficial: palmar, plantar, penile Deep: abdominal, extra-abdominal, intra-abdominal
Benign mimickers of prostate carcinoma
Histo structures: Cowper’s glands, paraganglion, seminal vesicle, mesonephric glands Atrophy, partial atrophy Inflammation Granuloma Xanthoma Malakoplakia
Variants of prostatic carcinoma mimicking benign lesions
WD prostatic carcinoma - adenosis Atrophic prostatic carcinoma - atrophy Foamy gland prostatic carcinoma - xanthoma PCA with inflammation - inflammation Signet ring PCA - Artifactual changes Pseudohyperplastic PCA - epithelial hyperplasia or HGPIN Clear cell PCA - granuloma Ductal adenocarcinoma - HGPIN
Inflammatory myofibroblastic tumour
spindled myofbiroblasts, fibroblasts and inflammatory infiltrate loosely arranged in edematous myxoid background with abundant BV and plasma cells, lymphocytes and eosinophils looks like granulations tissue or nodular fasciitis can have fibromatosis like cellular areas can have bulging of spindle cells into vascular spaces or surroundeing BV
What specific histological types of breast ca have good prognosis? Poor prognosis?
Good: mucinous, tubular ca Bad: metaplastic, micropapillary
Fanconi anemia
Clinical features:
- pancytopenia
- prenatal growth retardation
- hypoplastic or missing thumbs
- arm deformation
- brown pigmentation of skin
- risk of AML, pgrogressive BM failure
Cytogenetic manifestation: increased chromosome breakage detected by mitomycin C and diepoxybutane
Bloom syndrome
Clinical manifestation:
- growht retardation
- butterfly rash on face
Cytogenetic manifestation: increased siter chromatid exchagne in response to UV from abN DNA ligase activity
Angelman syndrome
Severe MR, developmental delay, large mouth, prognathia, ataxia, seizures DiGeorge syndrome
DiGeorge syndrome
Characteristic facies, cleft palate, heart defect, hypoplasia of the thymus and parathyroids, severe hypocalcemia, seizures
CATCH 22
cardiac defect
abnormal facies
thymic hypoplasia
cleft palate
hypercalcemia
22q11
Painful cutaneous lesions
LEND AN EGG leiomyoma eccrine spiradenoma neuroma dermatofibroma angiolipoma neurolemmoma/schwannoma endometrioma glomangioma granular cell tumour
Ichthyosis
Scaly skin, short stature, hypogonadism, MR
Kallmann syndrome
Hypogonadism, inability to smell
Langer-Giedion syndrome
Craniofacial dysmorphism, skeletal abnormalities, mild to severe mental deficiency
Lissencephaly
Smooth brain, profound retardation, seizures
Miller-Dieker syndrome
Lissencephaly, microcephaly, high forehead, small nose, micrognathia, low-set ears
Prader-Willi syndrome
Hypotonia at birth, almond-shaped eyes, moderate to severe MR, absent sense of satiation leading to overeating, small hands and feet, hypogonadism
Retinoblastoma
Tumors of the retinoblast cells of the eye
Rubinstein-Taybi syndrome
Beaked nose, prominent columella, hypoplastic maxilla, downslanted palpebral fissures, broad thumbs and first toes, MR, speech delay
Smith-Magenis syndrome
Brachycephaly, midface hypoplasia, broad nasal bridge, prominent jaw, short broad hands, hyperactivity, delayed speech, self-destructive behavior, MR
Velocardiofacial syndrome
Palatal defects, hypoplastic alae nasi with long nose, learning disability, congenital heart disease
WAGR
Wilms tumor, aniridia, genitourinary defects, and mental retardation
Williams syndrome
Low IQ, hypersensitivity to sound, blue eyes with stellate pattern in the iris, prominent lips, hoarse voice, supravalvular aortic stenosis or other cardiac defect, hypercalcemia, premature aging of the skin
Li-Fraumeni
25X greatere chance of devloping a malignant tumour by age 50 Varied spectrum of tumours Sarcomas Breast cancer Leukemia Brain tumours Carcinomas of the adrenal cortex
Ataxia telangiectasia
Clinical manifestation: ataxia with CNS degeneration, telangiectasia on face, deficiency in cellular immunity, degenerative, growth retardation, leukemias and solid tumours
Cytogenetic” increased spontaneous breakage and increased rings, triradials, and translocations, particularly with 7 and 14, induced with bleomycin or ionizing radiation
Xeroderma pigmentosum
Clinical manifestations: sensitivity to sun, neurological abnormalities, ataxia and spasticity, melanoma
Cytogenetic: increase in SCE and chromsome rearrangements in response to UV light
Cockayne syndrome
- Dwarfism
- premature aging
- microcephaly
- neurological deficit
- pigmentary degeneration
- deafness
- MR
- increased skin cancer rates
Gorlin syndrome
PTCH gene, AD, 9q
The major criteria consist of the following:
- more than 2 BCCs or 1 BCC in a person younger than 20 years;
- odontogenic keratocysts of the jaw
- 3 or more palmar or plantar pits
- ectopic calcification or early (<20 years) calcification of the falx cerebri
- bifid, fused, or splayed ribs
- first-degree relative with NBCCS.
The minor criteria include the following:
- macrocephaly.
- congenital malformations, such as cleft lip or palate, frontal bossing, eye anomaly (cataract, coloboma, microphtalmia, nystagmus).
- other skeletal abnormalities, such as Sprengel deformity, pectus deformity, polydactyly, syndactyly or hypertelorism.
- radiologic abnormalities, such as bridging of the sella turcica, vertebral anomalies, modeling defects or flame-shaped lucencies of hands and feet.
- ovarian and cardio fibroma
- medulloblastoma (the latter is generally found in children below the age of two
Three syndromes with vascular connective tissue complications.
- Marfan syndrome
- Leoys Dietz syndrome
- Ehlers-Danlos syndrome
Marfan syndrome
- glycoprotein fibrillin-1, FBN-1, 15q
- AD
- Manifestations:
- skeletal: tall, long extremities and long fingers and toes, lax joints,dolichocephalic, frontal bossing, prominent supraorbital ridging, kyphosisi, scoliois, rotation/ slipping of dorals or lumbar vertebrae, pectus excavatum
- Ocular: ectopia lentis
- Cardiovascular: mitral valve prolapse, cystic medionecrosis, aortic incompetence, dissection
- Skin: laxity of skin
Loeys-Dietz syndrome
- TGFBR1 and TGFBR2
- AD
- Manifestations:
- skeletal: pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus
- Vascular: aortic aneurysms
- LSD1 ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis
- LSD2 velvety and translucent skin; easy bruising; widened, atrophic scars
Ehlers-Danlos syndrome
- defect in fibrillar collagen
- six variants:
- classical (AD)
- skin and joint hypermobility, atrophic scars, easy bruising
- protein: type V collagen
- kyphoscoliosis (AR)
- hypotonia, jiont laxity, congenital scolioisi, ocular fragility
- protein: lysyl hydroxylase
- vascular (AD)
- thin skin, arterial or utering rupure, bruising, small joint hyperextensibility, bowel perforation
- protein: type III collagen
- arthrochalasia (AD)
- severe joint hypermobility, skin changes, scoliois, bruising
- protein: type I collagen
- dermatosparaxsis (AR)
- severe skin fragility, cutis laxa, bruising
- protein: procollagen-N-peptidase
- classical (AD)
- hypermobility (AD)
- joint hypermobility, pain, dislocation
Fanconi syndrome
- Syndrome of loss of multiple solutes at the proximal convoluted tubule of the kidney
- The clinical features of proximal renal tubular acidosis are:
- Polyuria, polydipsia and dehydration
- Hypophosphatemic rickets (in children) and osteomalacia (in adults)
- Growth failure
- Acidosis
- Hypokalemia
- Hyperchloremia
- Other features of the generalized proximal tubular dysfunction of the Fanconi syndrome are:
- Hypophosphatemia/phosphaturia
- Glycosuria
- Proteinuria/aminoaciduria
- Hyperuricosuria
Triad of Wegener’s granulomatosis
- Acute necrotizing granuloma
- Acute necrotizing or granulomatous vasculitis
- Renal disease - focal necrotizing crescentic GN
Sturge-Weber syndrome
- aka encephalotrigeminal angiomatosis
- venous angiomatous masses in cortical leptomeninges and ipsilateral facial port wine nevi
- mental retardation
- sz
- hemiplegia
- skull radioopacities
Olser-Weber-Rendu Disease
- aka hereditary hemorrhagic telangiectasia
- AD
- telangiectasia - skin and oral mucous membranes, respiratory tract, GI, GU tracts
*
Which hereditary disorders are characterised by angiomyolipoma?
NF1
VHL
AD polycystic kidney disease
Tuberous sclerosis
Which hereditary disorders are associated with a Wilms’ Tumour?
WAGR
Deny-Drash
Beckwith-Wiedemann
Trisomy 18
Multicystic dysplastic kidney
