Syndromes Flashcards
NF1 is on chromosome
17q11.2
17q11.2 protein product?
Neurofibromin
Hallmark findings of NF1?
i. Multiple Café au lait macules
ii. Neurofibromas (Plexiform)
iii. Lisch nodules
NF1 associated bone lesion?
Sphenoid wing dysplasia
NF1 associated tumors? Soft tissue (6): Carcinoma: Heme: GI:
Soft tissue: MPNST, Rhabdomyosarcoma, non ossifying fibromas, Glomus tumors, Carcinoid tumors, Pheochromocytoma
GI: ampullary adenoCA, GIST (lacks kit), somatostatinoma, gangliocytic paraganglioma, neurofibrmas
Heme: JMML
Breast cancer
NF1 associated brain tumors?
Astrocytoma and optic/brainstem gliomas
NF2 is on chromosome?
22q12; Merlin
Hallmark findings of NF2?
Bilateral vestibular Schwannomas, meningiomas, ependymomas,
Other NF2 associated tumors?
Retinal hamartomas, Astrocytomas
TS1 is on chromosome? name?
9p34 ( Hamartin)
TS2 is on chromosome? name?
16p13.3 (Tuberin)
Major features of TS?
Soft tissue/skin (6)
CNS/eye (4)
Heart
- Connective tissue nevus (Shagreen patch)
- Facial angiofibromas (adenoma sebaceum)
- Lymphangioleiomyomatosis (LAM)
- Angiomyolipoma
- Subungual and periingual fibromas (Koenen tumor)
- Hypomelanocytic macules (ash leaf spots)
- gycogen acanthosis
- Retinal hamartomas
- Cerebral cortical tuber
- Subependymal nodule
- Subependymal giant cell astrocytoma (SEGA)
- Cardiac rhabdomyoma
Name chromosomes for VHL
3p25-26
Characteristic findings of VHL
CNS/eye: Kidney: Pancreas: Adrenal: GU:
- Hemangioblastomas in CNS and retina
- Endolymphatic sac tumor
- Clear cell RCC,
- serous Cysts in pancreas and kidney (VHL1)
- Pancreatic islet cell tumors
- Pheochromocytoma (VHL2)
- Papillary cystadenoma of epididymis
Sturge-Weber characteristic finding?
Port wine stain on ophthalmic division of trigeminal nerve
Other sturge-weber findings?
meningeal angiomatosis
brain calcifications
seizures
mental retardation
FAP chromosome? gene name?
5q21-22, APC gene
FAP findings?
Colon: SI: Stomach: Liver: Pancrease/bile duct: Soft tissue: Bone: Teeth: Eye: Endocrine system: Brain (Turcot syndrome): Head and neck:
Colon: >100 polyps
SI: Duodenal ampullary adenoma, periampullary adenocarcinoma
Stomach: fundic gland polyp
Liver: Hepatoblastoma
Pancrease/bile duct: Adenocarcinoma
Soft tissue: Fibromatosis
Bone: osteomas
Teeth: impaction
Eye: Congenital hypertrophy of retinal pigment epithelium (CHRPE) (Earliest manifestation)
Endocrine system:
Papillary thyroid carcinoma, cribriform morular variant, in women
Adrenal cortical neoplasms
Pancreatic islet cell neoplasms
Rare reports of parathyroid and pituitary adenomas
Brain (Turcot syndrome):
Hereditary CRC & brain tumor
FAP patients: Medulloblastomas
Lynch patients: Gliomas
Head and neck: Nasopharyngeal angiofibroma
Gardner chromosome? gene?
5q21-22, APC ( same as FAP)
Gardner finding?
Soft tissue:
Bone:
GI
Eye
- Desmoid fibromatosis (intrabadominal)
- Epidermal inclusion cysts
- Osteoid Osteomas (mandibular and maxillary)
- Chronic polyps (can have malignant transformation)
- congenital hypertrophy of the retinal pigmented epithelium
Turcot Syndrome: chromosome? gene?
5q21-22, APC ( same as FAP)
Adenomatous colorectal polyps- attenuated FAP
Type 1: GBM with hereditary non-polyposis CRC (HNPCC)
- Mutations in mismatch repair genes (Hpms2; 7p22)
Type 2: Medulloblastomas in patients with familial adenomatous polyposis (FAP)
- Germlines mutations in APC gene (5q21)
Ollier Synd.
Multiple endondromatosis
Maffucci Syndrome:
Spindle cell hemangio(endothelio)ma + enchondroma
McCune Albright Synd: Mutation?
GNAS1 gene mutation with mosaic distribution
McCune Albright Synd: Triad?
- Café au lait skin pigmentation
- Polyostotic fibrous dysplasia
- Hyperfunctioning endocrinopathies
- Cases precocious puberty
- hyperthyroidism
- GH excess
- Cushing syndrome
- follicular thyroid carcinoma
- PTC
Mazabraud Synd:
- Multiple cutaneous or IM myxomas
- Polyostotic fibrous dysplasia
Basal cell nevus syndrome, Gorlin Synd: Mutation? inheritance?
AD
Germline mutations of PTCH gene (chromosome 9q22.3):
SONIC HEDGEHOG (SSH) PATHWAY
Basal cell nevus syndrome, Gorlin Synd: Assoc.?
Skin
Soft tissue
Bone
Brain:
- Multiple basal cell carcinomas
- Dyskeratotic pits of the palms/soles
- fibromas, cardiac/ovary
- Rhabdomyosarcomas
- Odontogenic keratocysts (jaw)
- Bifid ribs
- Intracranial calcifications
- Macrocephaly
- Nodular/desmoplastic medulloblastomas
Li-Fraumeni Syn: mutation?
p53
Li-Fraumeni Syn: assoc?
osteosarcoma (1000x risk)
medulloblastoma
Unusual thyroid follicular cell tumors with marked nuclear pleomorphism
Carney’s Synd.:
NAME : Nevi, Atrial Myxoma, Myxoid Neurofibroma, Ephelides
LAMB: Lentigenes, A, M, Blue nevi
Myxomas : Breast, Gyn, skin
Endocrine overactivity (pituitary adenoma, follicular adenoma, Primary Pigmented Nodular adrenocorital Disease)
Melanocytic schwannomas
Large cell calcifying sertoli cell tumors (multiple, bilateral)
Carney’s Triad:
Multiple GIST (with SDH mutation)
Functioning, extra-adrenal paraganglioma
Pulmonary chondromas
Carney Complex: Mutation? inheritance?
AD
PRKAR1A mutation on Ch 17q
Cowden dz: Mutation? inheritance?
PTEN mutation, 10q
AD
Cowden: Tumors?
Brain
Breast
Thyroid
Uterus
Soft tissue
Skin
Malformation
- Cerebellar dysplastic gangliocytoma (Lhermitte-Duclos lesion): PATHOGNOMONIC
- Benign and malignant tumors of breast, uterus, thyroid
- Breast cancer: early onset (38-46 y/o)
- Follicular adenoma/carcinoma
- Hamartomas
- Papillomas
- Lipomas (lipomatosis)
- Oral fibromas
- ganglioneuromas
- gycogen acanthosis
- Trichilemmomas
- Malf of GU tract
- Palmoplantar keratosis and hyperkeratotic pits
Ataxia telangiectasia:mutation?
ATM, chrom 11
Ataxia telangiectasia:assoc?
Cerebellar Ataxia Oculocutaenous telangiectasia Sinopulmonary infection Hypoplasia of thymus, tonsils, adenoids Combined B and T cell defect Deficient IgA with high AFP and CEA Hematolymphoid malignancy (100x) Increased cancer risk
BRCA-1
17q21, Tumor suppressor gene Medullary breast cancer Colon Ovary Prostate
BRCA-2
13q12-13 Possible role in DNA repair Male breast Pancreas Ovary Prostate
Lynch Synd (hereditary nonpolyposis colorectal cancer, HNPCC, Synd): Mutation? inheritance?
AD
Caused by defects in DNA mismatch repair (MMR) gene
MLH-1, MSH-2, MSH-6, PMS-2
Lynch Synd (hereditary nonpolyposis colorectal cancer, HNPCC, Synd): Lesions?
- Progress from sessile serrated adenomas
- large exophytic mass in right colon
- often have mucinous differentiation
- lack central dirty necrosis
- tumor infiltrating lymphocytes
- peritumoral “Chronlike” nodular lymphoid
reaction - Pushing tumor margin
Klinefelter Syndrome
Leydig cell tumors
Autosomal Dominant Polycystic Kidney Disease (ADPKD): Mutation? inheritance?
AD
Mutations in genes PKD1 (in Ch16) and PKD2 (in Ch4); affecting polycystin-1 and polycystin-2
Autosomal Dominant Polycystic Kidney Disease (ADPKD): Lesions?
Multiple renal cysts Liver cysts (50%) (no dysfxn) Pancreatic cysts Cardiac valve abnormalities, MVP (~25%) Berry aneurysms (5-8%
Wiskott-Aldrich Syndrome:
Dense granule disorder X-linked defects in WASP gene Increased IgE Triad: - Thrombocytopenia with small platelets - Eczema - Immunodeficiency
Birt-Hogg-Dube Syn
AD
BHD (FLCN) gene on Ch17p11.2, folliculin
Assoc w:
- RCC (mixed chromophobe/oncocytoma)
- Cystic pulmonary lesions with recurrent
spontaneous pneumothorax
- Multiple cutaneous fibrofolliculomas
- Acrochordons
- TrichodiscomasMuir-Torre Syn
Tumors:
- Sebaceous neoplasms:
- Well differentiated sebaceous carcinoma
- Sebaceous adenomas - Higher risk of other hereditary nonpolypopsis CRC-related tumors
Peutz-Jeghers Syndrome
Oral:
GI:
Malignancies of the:
AD; LKB1/SKT11 gene (19p13.3)
Perioral pigmented macules
GI hamartomatous polyps
Increased risk of benign and malignant neoplasms: (not the polyps themselves)
- Pancreatic Ca (1oo fold increase)
- Breast Ca
- Ovarian sex cord tumor with annular tubules
(SCTAT)
- Less common: adenoma malignum of the uterine
cervix, sertoli cell tumors of the testis
WAGR Synd. (WT-1)
How is it acquired?
Stands for?
2HITS, germline and a frameshift/nonsense mutation on 11p13 locus: contains WT1 and PAX6 genes
Tumors:
- Wilms tumor (Nephroblastoma)
- Aniridia
- Genital abnormalities
- Mental Retardation
Denys-Drash Synd
Germline mutation in the zinc-finger region of WT1 protein
Assoc with: Male pseudohermaphroditism Diffuse mesangial sclerosis Tumors: Wilms tumor (Nephroblastoma) Gonadoblastoma
Fanconi anemia
Skeletal:
Heme:
Population:
AR Chromosomal breakage syndrome
Absent thumb, microcephaly
Macrocytic anemia –> pancytopenia
AML (600x)
MDS (5,000x)
elevated Hb F
South Africans
MEN1 (Wermer syndrome)
AD
Chrom 11, MEN1 gene
Pituitary adenoma (majority are prolactinoma) Hyper parathyroid Pancreatic endocrine tumor ( gastrinoma->ZE ,> insulinoma > glucagonoma)
Juvenile polyposis
SMAD4/DPC4 (40%) Increased risk of CRC
Associated: Hydrocephalus Pulm AVM Cleft palate Polydactyl Meckels Malrotation
Alpha 1 antitrypsin disease
SERPINA (SERPINC1 is antithrombin deficiency)
Chromosome 14 AR
PiZZ is the abnormal genotype
PiMM is the normal
Men 2a (Sipple syndrome)
MTC
Pheo
Parathyroid adenoma/hyperplasia
RET 10q12 EXON 10 & 11
MEN2B
MTC pheo Mucosal neuromas "Marfanoid" body Medullated corneal nerve fibers Ganglioneuromatosis
RET 10q12 EXON 16
Familial paraganlioma
SDH Succinate Dehyrdrogenase
Alports
COL4A5, Xp22.3
a5 chain of type 4 collagen
Glomerulonephritis, Ocular lesions, sensorinueral hearing loss
Name syndrome
Healthy young men, sudden death during sleep
Southeast asia
Mutation in SCN5A
Brugada syndrome
8 mutations in total
SCN5A, GPD1L, CACNA1C and others
Name syndrome
Healthy young men, sudden death during physical activity
Fibrous and fatty replacement of the right ventricle
Arrhtymogenic right ventricular dysplasia
Whats that gene/chrom
Long QT Exercise triggered (especially swimming)
LQT1 on 11p15.5 - most common QT
Whats that gene/chrom
Long QT
Auditory stimulus or emotional stimmulus triggered arrhythmias
LQT2 on 7q35-36
Name the syndrome and mutation
Healthy young men, sudden death during physical activity
Heart shows hypertrophy with disproportionate thickening of the ventricular septum
Hypertrophic cardiomyopathy : MYH7
AD
MYH7 also seen in AD dilated cardiomyopathy
Pulmonic stenosis
Right sided heart defects
prolonged coagulations
PTPN11
Noonan syndrome
Cholestasis in the neonatal period Bile duct paucity Heart defects: Pulm artery stenosis, Tetraology, ASD, VSD Facial dysmporphism Butterfly vertebrae JAG1 AD
Alagille syndrome
Trisomy 21: name the heart defect
malformation of the endocardial cushion resulting in the membranous VSD
Biscuspid aorta
Coarctation of aorta
lymphangioma
shield chest
Turner 45 X
Males with hypogonadotropic hypogonadism
anosmia
Xp22.3, KAL1 gene
Kallmann syndrome
Hirschprung disease seen in
Trisomy 21
NF1
MEN 2A
Epistaxis in children Skin lesions in adolescence GI bleed in adults AD ENG gene or ACVRL1 gene
Osler-Weber-Rendu syndrome
hereditary hemorrhagic telangiectasia
Malabsorption in neonates Paper thin wall of the small bowel Villus blunting mucosal atrophy Apical intracellular inclusions (PAS +) AR
Microvillus Inclusion Disease
VACTERL stands for
Vertebral Anal Cardiac Tracheal Esophageal Renal Limb
Segmental dilation of the intrahepatic bile ducts
Recurrent stone formation
Bacterial cholangitis
Caroli disease
Name syndrome and lab finding:
Cirrhosis pancreatic fibrosis hypogonadotrophic hypogoandism Cardiomyopathy Bronze skin
Hemochromatosis , HFE on 6p21.3 with C282Y or H63D mutation
AR
Low hepcidin
Hepcidin degrades ferroportin (an iron chanel needed for Fe absoprtion)
Name syndrome and lab finding:
neuropsychiatric disease
hemolysis
kayser-Fleischer rings
Liver bx: glycogenated nuclei with steatosis and inflammation –> cirrhosis
Wilsons, AR
ATP7B - allows for copper to bind to Ceruloplasmin
Serum LOW ceruloplasmin and Copper
Urine High ceruloplasmin
Unbound ceruloplasmin is unstable and quickly degraded.
Mildly elevated unconjugated bili
Mutation of the 5 TATA box of the promotor UGT1A1 leading to deficient bilirubin glucuronosyltransferase
Gilberts
Elevated unconjugated bili
No glucuronosyltransferase activity? if <10?
Type 1 Crigler Najjar
Type 2 Crigler Najjar has about 10%
Elevated conjugated bili
Mutation in the MRP2 gene
Black but normal liver
Dubin Johnson
Elevated conjugated bili
Rotor
Name syndrome, gene and mutation
Meconium ileum Nasal polyps Male infertility caused by the congenitl bilateral absence of the vas deference Biliary obstruction --> liver disease Bronchitis and Pneumonia
Cystic Fibrosis
AR
CFTR on chrom 7q31.2
F508 mutation in 66%
AD
pancreatitis and marrow failure
chromosomal breakage syndrome affecting mitochondrial DNA
Marrow shows sideroblastic anemia with vacuolization
Pearson syndrome
AR Exocrine pancreatic insufficiency (Fatty metamorphosis) Aplastic anemia short stature reticular dysgenesis SBDS (7q21)
Shwachman-Diamond syndrome
Mutation in the MAPT gene that encodes microtuble associated protein tau leads to
Familial Pick Disease aka Frontotemporal demntia with parkinsonism
mutation in the amyloid precursor protein on chrom 21 leads to ?
Alzheimer disease
Late or usual Alzhemier disease is associated with?
E4 allele of the APOE gene
> 40 copies of the CAG repeat in the HTT gene on 4p causes?
Huntingtons disease
Migraine headaches with TIA
Progress to dementia
MRI: hyperintense lesion in the periventircular white matter
Vessels show granular eosinophilic medial deposits
Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL)
AD peripheral neuropathy
duplication of 1.5Mb region of DNA on 17p12 containing PMP22 gene
BX: prominent onion bulb formation
Charcot Marie Tooth
X linked Recessive calf hypertrophy onset before 5 cardiomyopathy Bx: scattered hypereosinophilc small rounded fibers with negative staining with dystrophin
Duchenne muscular dystrophy
DMD Xp21
Muscular dystrophy with AD trinucloetide repeat disorder
Myotonic muscular dystrophy MMD
Name syndrome
Large for gestational age Polyhydramnios Omphalocele Organomegaly Renal/adrenal anomalies Wilms Hepatoblastoma
Beckwith-Wiedmann syndrome chrom 11
