Patozone

Abernethy Syndrome

Alagille syndrome

Allgrove (triple A) syndrome

Alport's syndrome

Angelman

Ataxia-Telangiectasia

Austrian's syndrome

Basal Cell Nevus Syndrome (Gorlin syndrome)

Behcet disease

Beckwith-Wiedemann syndrome

Biliary atresia-splenic malformation syndrome

Birt-Hogg-Dube

Bloom syndrome

Blue Rubber Bleb Nevus Syndrome (BRBNS)

Brooke-Spiegler syndrome

Brugada syndrome

Caplan syndrome

Carney complex (CNC)

Carney triad

Carney-Stratakis syndrome

Cogan syndrome

Congenital Adrenal Hyperplasia

Congenital Nephrotic syndrome of the Finnish type

Cowden syndrome

CREST syndrome

Cri du chat

Criggler-Najjar syndrome

Cronkhite-Canada syndrome

Dejerine-Roussy syndrome (thalamic pain syndrome)

Denys-Drash syndrome / Frasier syndrome

DiGeorge syndrome

Down syndrome

Dubin-Johnson syndrome

EBV-assoc tumors

Edward syndrome

Familial retinoblastoma

Familial Adenomatous Polyposis (FAP)

Familial Atypical Multiple Mole Melanoma Syndrome

Familial Autosomal Dominant Focal Segmental Glomerulosclerosis

Familial Autosomal Recessive Corticosteroid-Resistant Nephrotic Syndrome

Fanconi's anemia

Felty's syndrome

Ferguson-Smith syndrome

Gardner syndrome

Gilbert syndrome

Goldenhar syndrome

Goltz syndrome

Gorlin syndrome

Griscelli syndrome

Hereditary Hemorrhagic Telangiectasia

Hereditary Leiomyoma and Renal Cell Carcinoma syndrome (HLRCC)

Hereditary NonPolyposis Colorectal Cancer (HNPCC; Lynch syndrome)

Hereditary Papillary Renal Cell Cancer (PRCC)

Hereditary diffuse gastric cancer syndrome

Hermansky-Pudlak syndrome

HELLP syndrome

HHV-8 assoc tumors

HIV-assoc tumors

Holt-Oram syndrome (heart-hand syndrome)

Hyper-IgE syndrome

INI-negative tumors

Juvenile polyposis syndrome

Kallman syndrome

Kasabach-Merritt syndrome

Kearns-Sayre syndrome

Klippel-Trenaunay syndrome

Lennox-Gastaut syndrome

LEOPARD syndrome

Leser-Trelat syndrome

Li-Fraumeni syndrome

Long QT syndrome

Maffucci's syndrome

Mazabraud's syndrome

McCloud syndrome

McCune Albright syndrome

Meckel-Gruber syndrome

Meigs syndrome

Miller-Dieker syndrome

MonoMAC Syndrome

Muir-Torre syndrome

Multiple Endocrine Neoplasias (MEN 1,2A and 2B)

MYH-associated Polyposis (MAP)

Nail-patella syndrome

Neurofibromatosis type 1

NF2

Noonan syndrome

Ollier's syndrome

Pearson syndrome

PEComa family

Peutz-Jeghers syndrome

Pierson syndrome

Pleuropulmonary blastosis familial tumor syndrome

POEMS syndrome - see Lymphoid neoplasms

Polycystic Ovarian Syndrome (PCOS)
Prader-Willi

Reed's syndrome

Retinoblastoma (Rb)

Rhabdoid Tumor Predisposition Syndrome (RTPS)

Rombo syndrome

Rotor syndrome

Ruvalcaba-Myhre-Smith syndrome

Schwachman-Diamond syndrome

Small round blue cell tumors

Smith-Lemli-Opitz syndrome

Smith-Magenis syndrome

Sturge-Weber disease

Stein-Leventhal syndrome

Stiff Person Syndrome (SPS)

Tuberous Sclerosis

Turcot syndrome

Turner syndrome

VATER/VACTERL syndrome

von Hippel-Lindau syndrome

WAGR syndrome

Weber-Christian disease

WHIM syndrome

Williams syndrome

Wiscott Aldrich syndrome

Wolf syndrome

Zellweger syndrome

Zollinger-Ellison Syndrome

 

***BONUS POINTS***

Tumor suppressor genes

Oncogenes

Abernethy Syndrome

 

Absent portal vein from birth c shunting of intestinal and splenic blood around liver to renal or hepatic veins

- micro: absent portal veins in small and medium-sized portal tracts c occasional hypoplastic portal veins in larger portal tracts

- nodular regenerative hyperplasia possibly seen

- hepatic arteries usually hypertrophied c prominent muscular coats

- mass esions can develop, such as focal nodular hyperplasia and HCC in non-cirrhotic livers

 

 

Alagille syndrome

- aka arteriohepatic dysplasia, syndromic paucity of bile ducts

 

AD, JAG1 mutation

- assoc c bile duct paucity, pulmonary artery stenosis, tetralogy, atrial septal defects, aortic stenosis, coarctation

- facial dysmorphism (broad forehead, widely spaced eyes, small mandible, prominent ears, imparting an overall triangular profile), butterfly vertebrae, posterior embryotoxin of the eye, and congenital heart disease (esp peripheral pulmonic stenosis)

 

 

Allgrove syndrome

 

aka triple A syndrome

 

AR; achalasia, alacrima (disorders of tear secreation), and adrenocorticotropic hormone-resistant adrenal insufficiency

 

Alport's syndrome

 

Mutation in type IV collagen leads to split BM

- assoc c nerve disorders, ocular disorders, deafness

 

Sx: hematuria, slowly-progressive renal failure, hearing loss

Genes: X-linked recessive, COL4A5 mutation on Xp22.3, which encodes a5 chain of type IV collagen

EM: thickening / thinning of GBM c unique "basketweave" appearance

 

Dx: skin or renal bx, absence of a5 chain of type IV collagen

 

EM: thin, disrupted and inhomogeneous lamina densa, sometimes appearing multilaminar

 

Angelman

 

Maternal 15q11.2

- hyperactivity, inappropriate laughter, aphasia, ataxia, MR, seizures

 

Ataxia -Telangiectasia

 

AR, Ataxia Telangiectasia Mutated (ATM), 11q22-23

- Defective DNA repair, inc sensitivity to x-ray

 

Ataxia, telangiectasias in eyes and skin, thymic hypoplasia and recurrent sinopulmonary infections

- Absent IgA, ↓ IgE, ↓ CD4 T-cells

- ↑ Lymphoreticular malignancies (ALL in kiddos, solid tumors in adults)

 

Austrian's syndrome

 

Triad: endocarditis, meningitis and pneumonia; endocarditis seen in alcoholics c pneumococcal endocarditis, not seen much anymore

 

Basal Cell Nevus Syndrome (Gorlin syndrome)

 

AD,  9q22, PATCHED gene

 

• Numerous BCCs

• Palmar-plantar pits, odontogenic keratocysts, calcification of falx, skeletal anomalies (bifid ribs), neurologic anomalies, lipomas, fibromas, medulloblastomas, ovarian cysts

Behcet disease

 

Oral ulcers, genital ulcers, uveitis; pathergy test positive

- incidence highest in Middle East, Far East, and Mediterranean

 

 

Beckwith-Wiedemann syndrome

 

sporadic or AD (3/20), WT2, 11p15

 

- Syndrome of diffuse overgrowth: high birth weight, macroglossia, organomegaly, hemihypertrophy, neonatal hypoglycemia

- Risk of embryonal tumors: Wilms tumor, hepatoblastoma, pancreatoblastoma,

 

 

Biliary atresia-splenic malformation syndrome

 

Polysplenia, asplenia, or double spleen

- some can have cardiovascular malformations (situs inversus, preduodenal portal vein, absent vena cava), intestinal malrotation, pancreatic anomalies

 

Birt-Hogg-Dube syndrome

 

AD, 17p11.2, BHD gene (folliculin)

 

Kidney cancer (multifocal, bilateral, hybrid oncocytoma and chromophobe renal cell carcinoma [HOCT, nearly 10/10]), renal and pulmonary cysts / pneumothorax, and fibrofolliculomas (trichodiscomas), acrocordon

 

 

Bloom syndrome

 

AR, BLM helicase, cr 15

 

Predisposed to cancer, but esp leukemia; also other developmental defects

 

 

Blue Rubber Bleb Nevus Syndrome (BRBNS)

 

assoc c multiple cutaneous (congenital) and GI hemangiomas

 

 

Brooke-Spiegler syndrome

 

Numerous trichoepitheliomas and cylindromas

- sometimes spiradenoma or spiradenoma / cylindroma overlap syndrome

 

Genes: mutations in the CYLD gene on cr 16q12-q13

 

Brugada syndrome

 

Most prevalent in southeast Asia

- presents in healthy young men as sudden death during sleep

- has characteristic ECG pattern

- Mutations in 8 genes (SCN5A, GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, HCN4)

 

Caplan syndrome

 

Rheumatoid arthritis c intrapulmonary rheumatoid nodules and pneumoconiosis

 

*** put a Cap in your lungs! ***

 

 

 

Carney Complex (CNC)

 

AD, 70% familial, Protein kinase A

 

CNC1: PRKARIA, 17q23-24, most common, also CNC2: CNC2, 2p16.

- protein kinase regulatory subunit-alpha gene

-- has null mutations in PRKAR1A which encodes cAMP-dependent protein kinase

 

Clinical Manifestations:

- Skin lesions: lentigines, epithelioid blue nevi

- Myxoma: heart, skin (angiomyxoma), and breast (FA)

- Psammomatous melanotic schwannoma, upper GI schwannomas

- Breast ductal adenomas

- Testicular large cell calcifying Sertoli cell tumor

- Endocrine: primary pigmented nodule adrenocortical disease (PPNAD); pituitary adenomas (GH, prolactin), thyroid follicular adenoma

 

***It's complicated, even for a Carney, to TAME a LAMB***

TAME: Testicular sertoli cell tumor, Adenomas (breast, pituitary, thyroid), (atrial, skin) Myxoma, Ephelides

LAMB: Lentigines, Adrenocortical dz, Melanotic schwannoma, Blue nevi

 

 

Carney Triad

 

GISTs, paraganglioma, pulmonary chondroma in young women

- epithelioid, germline, mets, resistant to imatinib

 

Genes: SHDB IHC negative, no SDH mutations

 

 

 

 

Carney-Stratakis syndrome

 

Multiple gastric epithelioid GIST, paraganglioma, and pheochromocytomas assoc c germline loss of SDH (succinate dehydrogenase complex)

- resistant to imatinib

- distinct from Carney triad

 

 

Cogan Syndrome

 

Vasculitis with keratitis and vestibulo-auditory symptoms

 

 

Congenital Adrenal Hyperplasia

 

Assoc c adrenal rest tumors of the testis (10/10), which are similar to Leydig cell tumors, but are bilateral and/or multifocal, assoc c dense fibrosis and dont have Reinke crystals

 

 

Congenital Nephrotic syndrome of the Finnish type

 

Nephrin affected on NPHS1 gene [19q13.1]

- nephrin is a key compoenent of the glomerular slit diaphragm

- affected children born with markedly enlarged placenta

- massive proteinuria begins in utero, nephrotic syndrome by 1 month of age

- EM is notable for an abnormal variation in the size of the slit pores (the space between podocyte foot processes) and rarefaction of the slit diaphragms

 

 

Cowden syndrome

- aka Multiple hamartoma syndrome

 

AD, PTEN/MMAC1 (a tumor suppressor), 10q23

- hamartomas involving organs from all 3 germ layers

 

• Hamartomatous colon polyps

• Facial trichilemmomas, storiform fibromas, mucosal lesions

- Macrocephaly

• Palmoplantar keratoses and hyperkeratotic pits

• Multiple lipomas and papillomas

• Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)

• Thyroid: multiple follicular adenoma or PTC

• Carcinomas of breast, thyroid, colon, endometrium, kidney

- may get immunologic abnormalities

 

Other PTEN syndromes: Ruvalcaba-Myhre-Smith (Bannayan-Riley-Ruvalcaba) syndrome, Proteus syndrome

 

CREST syndrome

 

A limited form of scleroderma (systemic sclerosis)

 

Calcinosis; Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias

 

Cri du chat

 

5p15.2 microdeletion

Abnormal cat cry, microcephaly, MR

 

Criggler-Najjar syndrome

 

Type I: Absent UDP-glucoronyl transferase (UGT1A1) causes unconjugated bilirubinemia (due to absent bilirubin conjugation), which is fatal in first few years of life

- absent conjugated bili

- negative urine bilirubin

- dec urine bilinogen

- light-brown poop

 

Type II (Arias syndrome) less severe (UDP-G just decreased, not absent and can be tx'd c phenobarbitol

 

Sx: jaundice, kernicterus, inc unconjugated bilirubin

 

Tx: plasmaphoresis, phototx

 

 

Cronkhite- Canada syndrome

 

Non-familial; high mortality c GI bleeds, prolapse and infx

Lots of gastric hyperplastic polyp-like cystically dilated lesions and more edematous (somewhat similar to juvenile polyposis) in sm / lg bowels, and may present c sx related to diarrhea

- inc risk of colorectal ca

- polyps spare the esophagus

- pts also c alopecia, onychodystrophy (from protein loss in mucoid diarrhea) and skin hyperpigmentation

Dejerine-Roussy syndrome

-aka thalamic pain syndrome

 

Numbness turns into chronic pain out of proportion to environmental stimulus (called allodynia or dysasthesia) after a cerebrovascular accident usually

 

 

Denys-Drash syndrome / Frasier syndrome

 

WT1 gene [11p13]

Not familial, WT1 point mutation (vs deletion seen in WAGR)

 

Wilms tumor (9/10), gonadoblastoma, male pseudohermaphroditism, diffuse mesangial sclerosis causing rapidly progressive renal failure

- renal bx shows mesangial sclerosis

- Frasier syndrome is similar but less severe, assoc c gonadoblastoma

 

DiGeorge syndrome

- aka velocardiofacial syndrome, Catch 22 syndrome, CHARGE sequence or Shprintzen syndrome

 

22q11 microdeletion, TBX1 gene. thymic aplasia / hypoplasia (immunodeficiency), parathyroid aplasia / hypoplasia (hypocalcemia and tetany), abnormal facial features, MR, 75% c cardiac abnormalities, esp conotruncal malformations (including tratralogy of Fallot, interrupted aortic arch, ventricular septal defects and truncus arteriosis)

 

*** CATCH 22 = Cleft palate, Abnormal facies, Thymic aplasia (T cell deficiency), Cardiac defects, Hypocalcemia from 22q11 microdeletion ***

 

*** CHARGE sequence = Coloboma, Heart malformation, choAnal atresia, mental Retardation, Genital hypoplasia, hEaring loss ***

 

Down syndrome (Trisomy 21)

 

Primary trisomy (95%), translocation (4%), mosaicism (1%)

50% of cases with structural cardiac anomalies, classically an endocardial cushion malformation causing a membranous ventricular septal defect

- can also get patent ductus arteriosus, atrial septal defect and AV septal defects

- can get AML M7 (acute megakaryoblastic leukemia) and transient myeloproliferative disorder (in 1/3, GATA1 genemutation), MALToma or ALL

- nearly all pts get Alzheimer-like dementia by age 40 yo

- inc risk of retinoblastoma, testicular tumors, brain tumor

- inc risk of duodenal obstruction / atresia, imperforate anus, congenital megacolon

- hypoplastic maxilla

- slanting palpebral fissures

- abundant nuchal skin

- hypotonia

- Absent Moro reflex

 

Dubin-Johnson syndrome

 

Defective canalicular multiple organic anion transporter (cMOAT)

- prob c conjugated bilirubin excretion leading to conjugated hyperbilirubinemia

Liver appears grossly black

B9

 

Rotor's syndrome is similar to Dubin-Johnson but is milder and does not cause a black liver

*** Get Closer, Deeper Romance ***

*** Gilbert, Cirggler-Najjar, Dubin-Johnson Rotor syndrome ***

 

EBV-assoc tumors

 

Lymphomatoid granulomatosis, nasal type extranodal NK/T-cell lymphoma, (Mixed cellularity) classical Hodgkin Lymphoma, plasmablastic lymphoma, AngioImmunoblastic T-cell Lymphoma, Post-Transplant Lymphoproliferative Disease (PTLD), Infectious mononucleosis (enlarged LNs), X-linked lymphoproliferative disorder, primary effusion lymphoma, oral hairy leukoplakia

- EBV+ DLBCL of the elderly, DLBCL assoc c chronic inflammation,  and DLBCL NOS

- EBER (nuclear) and LMP1 (cyto / mem) ISH testing done

- can also do ISH c BamHIW sequence of EBV DNA

- EBV-ISH (+) in lymphoepithelioma-like cholangiocarcinoma

 

Edward syndrome

(Trisomy 18)

 

Babies born small and with heart defects (ventricular septal defect, atrial septal defect, patent ductus arteriosus), short sternum, narrow pelvis, omphalocele, esophageal atresia, microcephaly with prominent occiput, narrow palpebral fissues, ptosis, micrognathia, cleft palate, clenched fists with overlapping 2nd and 5th fingers, absent radius, webbing of second and third toes, clubfoot or rocker bottom feet, severe intellectual disability, undescended testes in males

- can also have kidney defects, choroid plexus cysts in brain

- rate of dz inc c maternal age

- occurs in 1 in 5k births; higher chance of surviving to birth if female, the chance of having a second child with the dz after having one is ~1%

 

Familial retinoblastoma

 

At risk for osteosarcoma, rhabdomyosarcomas and rhabdoid tumors

 

 

Familial Adenomatous Polyposis (FAP)

 

AD, Adenomatous Polyposis Coli (APC) gene, 5q

- APC usually degrades the proto-oncogene B-catenin, so when APC aint workin B-catenin builds up in the nucleus

 

- Colorectal carcinoma (10/10 if dont get early total colectomy) with hundreds to thousands of adenomas

- Gastric polyps: fundic gland polyps (can be dysplastic though are inert)

- Small intestine: (prox duodenal) adenomas, peri-ampullary carcinoma (MCC death after total colectomy)

- Thyroid cancer (esp cribriform-morular variant of papillary)

- Desmoids (fibromatosis), fibromas on neck, osteomas, epidermoid cysts and pilomatrixomas, unerupted and supernumerary teeth

- medulloblastomas (Turcot's)

- juvenile nasopharyngeal angiofibromas

 

- may be "attenuated", which isnt as bad

 

 

Familial Atypical Multiple Mole Melanoma Syndrome

- FAMMM syndrome, B-K Mole Syndrome

 

AD, p16 mutation on CDK2NA (p21), CDK4 (21q14), CMM (1p)

 

>100 nevi, dysplastic / atypical nevi, inc risk of melanoma

- inc risk of pancreatic adenoca

 

Familial Autosomal Dominant Focal Segmental Glomerulosclerosis

 

- a-actinin, ACTN4 gene; also transient receptor potential cation channel 6 by TRPC6 gene

- onset of nephrotic syndrome in adolescence or young adulthood

 

Familial Autosomal Recessive Corticosteroid-Resistant Nephrotic Syndrome

 

- Podocin, encoded by NPHS2 gene

- onset proteinuria in early childhood

- dx: renal bx initially resembles minimal change disease but transforms into focal segmental glomerulosclerosis

 

Fanconi’s Anemia

 

AR, Ashkenazi Jews

- Chromosomal breakage syndrome, increased sensitivity to mitomycyin C, diepoxybutane

 

- Abnormal skin pigmentation

- Absent thumbs, microcephaly, short stature (bone hypoplasia)

- PRCA/MDS/Aplastic anemia (marrow hypoplasia)

- AML (mostly M4, M5) and other leukemias

- Carcinomas: skin, liver, stomach

- kidney and spleen hypoplasia

 

Renal Fanconi Syndrome

 

Proximal tubular dysfunction with numerous causes

- manifests as glycosuria, amino aciduria, phosphaturia, hypokalemia, and metabolic acidosis (bicarbonate wasting)

- inherited causes include cystinosis, tyrosinemia, and galactosemia (secondary tubular damage), and direct inheritance of tubular defects such as Dent disease (X linked recessive defect in the CLCN5 gene encoding a chloride channel)

 

Felty's syndrome

 

RA, splenomegaly, leukopenia c neutropenia

 

***FeLt your spleen, and it hurts (from the RA)***

 

 

Ferguson-Smith (multiple keratoacanthoma) syndrome

 

AD, MSSE gene, 9q22-31

Teen-onset ulcerative keratoacanthomas c spontaneous resoltion and recurrence

 

Gardner's syndrome

 

AD, 5q21, APC

 

Get FAP stuff and also assoc c osteoma (mandible of skull), odontomas, colon polyps (and colorectal ca), epidermoid cysts, congenital hyperplasia of retinal epithelium, fibromatosis of breast, supernumary teeth and lipomas, desmoid tumors, pilomatrixomas, and congenital hypertrophy of the retinal pigmented epithelium (CHRPE)

 

*** Gardners PEDO (Spanish for fart) after eating too much*** Pilomatrixomas, Epidermoid cysts, Desmoid tumors, Osteoma, too many teeth***

 

Assoc c FAP (inactivation of the APC tumor suppressor gene)

- has 100% chance of colonic tubular adenomas and colon cancer

- also see dental and ocular probs, multiple skin tumors (epidermal cysts, nuchal-type and desmoplastic fibromas, lipomas, leiomyomas) and extracolonic ca's (thyroid, hepatobiliary, CNS) - caused by cilia??

 

Gilbert's syndrome

 

AR c underactive bilirubin-UGT (mutations in the 5' TATA box of the UGT1A1 promoter) causing prob c bilirubin uptake leading to unconjugated bilirubinemia

- No overt hemolysis

- Assoc c stress (fasting, viral illness)

- otherwise asymptomatic; may be present in up to 5% of whites

No tx necessary (avoid stress :) )

 

Goldenhar syndrome

 

- aka Oculo - Auriculo - Vertebral (OAV) syndrome; hemifacial microsomia

 

Abnormal development of first and second branchial arches

- abnormally developed ear, nose, soft palate, lip and mandible

 

See limbal dermoids, preauricular skin tags, and strabismus

 

 

Goltz syndrome (Basal cell nevus syndrome)

 

AD, PTCH

 

Goltz syndrome

- aka focal dermal hypoplasia

 

Pts have focal hair loss, abnormal nails and skeletal abnormalities

 

Micro: skin c slightly papillated epidermis overlying adipose tissue c no discernable dermis

 

 

Gorlin syndrome

- nevoid basal cell carcinoma syndrome (NBCCS)

 

AD / sporadic, mutation to PTCH gene cr 9q22.3

 

Sx: 2+ basal cell cas before age 20, body overgrowth, jaw keratocystic odontogenic tumor (KCOT or OKC), ovarian fibromas, congenital skeletal abnormalities, palmoplantar pits, desmoplastic medulloblastoma, other cancers (cardiac)

 

 

Griscelli Syndorme

 

A rare autosomal recessive disorder characterized by albinism (hypopigmentation) with immunodeficiency that usually causes death by early childhood

- there are 3 different classifications of the form of disorder

 

 

Hereditary Hemorrhagic Telangiectasia

- aka Rendu-Osler-Wber syndrome

 

AD, ACVRL1 (ALK1,    12q11-14) or ENG (endoglin, 9q33-34), both involved in TGF-B pathways

 

Aneurysmal telangiectasia in lots of organs (skin and mucosal surfaces [GI, resp, UT, and visceral organs])

- complicated by bleeding

 

Hereditary Leiomyoma and Renal Cell Carcinoma syndrome (HLRCC)

 

AD defect in Fumarate hydratase (FH), 1q42-43

 

PRCC type 2 c leiomyomas (cutaneous and uterine c distinct cytologic features

- can use IHC to show loss of FH

 

 

Hereditary NonPolyposis Colorectal Cancer (HNPCC)

- aka Lynch syndrome (though technically HNPCC is a more clinical diagnosis and Lynch syndrome is only confirmed after molecular dx)

 

AD dominant mutation of DNA mismatch repair genes, Microsatellite Instability (MSI)

 

DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2 and EPCAM

*** Think of them in pairs, with the lower one getting messed up first: SH's go together; MLH and PMS go together; abnormality in MLH -> PMS abnormality, MLH1 -> MLH6 abnormality ***

 

Lynch I = colon cancer

 

Lynch II: Colon > endometrial > ovary, breast

 

Features of colon ca:

- young pts, tubular adenoma-assoc

- rt-side of colon, large size

- poorly differentiated, often trabecular pattern

- mucinous/colloid differentiation, signet ring cells

- prominent tumor-infiltrating lymphocytes (TIL), peri-tumoral nodular lymphoid infiltrate

- medullary-like, well-circumscribed pushing margin

- LS related ovarian ca: clear cell type, younger age group (45 yo)

 

- 80% lifetime risk of CRC, 6/10 get endometrial, ~1/10 ovarian

- other cancers: stomach, pancreatobiliary, urothelial of upper tract (esp c inverted growth)[1/3], sm bowel, brain, skin (sebaceous adenomas, carcinomas, keratoacanthomas)

- prox colon always involved

 

Amsterdam criteria: 3-2-1

3 relatives (1 1st degree) c any HNPCC carcinoma; 2 generations, 1+ carcinoma in person younger than 50 yo

 

IHC testing can be done using MLH1, MSH2, MSH6, PMS2

- any nuclear positivity, and it is considered intact

Review  algorithm NEJM 352:1851, 2005

 

Genes: hMLH1 is mutated in up to 3/20 sporadic colorectal ca's, so other genes should be tested to be more certain of the diagnosis of Lynch syndrome

- MSH2 can be deleted through a deletion of the 3' end of EPCAM gene which causes methylation induction of the MSH2 promoter

 

 

Hereditary Papillary Renal Cell Cancer syndrome (PRCC)

 

AD defect in MET (via Hepatocyte Growth Factor), 7q34

 

Multiple bilateral PRCCs

 

 

Hereditary diffuse gastric cancer syndrome

 

AD CDH1 (E-cadherin) gene mutation

 

Diffuse gastric ca, lobular breast ca

 

 

Hermansky-Pudlak syndrome

 

Pts have oculocutaneous albinism (legally blind) assoc c bleeding diathesis and pulmonary fibrosis and colitis and lysosomal dysfunction

- common in Puerto Ricans

 

EM: Paucity of dense bodies (DB), necessary in the second phase of platelet agg

 

 

HELLP syndrome

 

Hemolysis, Elevated Liver enzymes, Low Platelets

 

- have epigastric or upper rt quadrant pain or heartburn, malaise, nausea/vomiting

- 1/5 get DIC (disseminated intravascular coagulation), more get renal failure (??)

 

 

 

HHV-8 assoc tumors

 

Kaposi sarcoma

Multicentric Castleman's disease (and plasmablastic lymphoma

Primary effusion lymphoma

 

 

HIV-assoc tumors

 

Kaposi sarcoma, (B cell) lymphoma, Mycosis fungoides, Oral / anorectal SCC, Plasmablastic lymphoma, Primary effusion lymphoma,

- classical subtype of Hodgkin (usually pts also have EBV infx), esp mixed cellularity or lymphocyte-depleted, sometimes nodular sclerosis (nodular lymphocyte predominant Hodgkin lymphoma is rarely if ever assoc c HIV)

 

 

Holt-Oram syndrome (heart-hand syndrome)

 

AD, TBX-5 [12q]

- characteristic heart and upper limb abnormalities

- upper limb malformations may involve the radius, thumb phalanges, or carpal bones and they range from severe (phocomelia) to minimal (subtle carpal bone deformities)

- usually bilateral and symmetrical and if asymmetrical the left is more severely affected

- Cardiac malformations most commonly take the form of septal defects, especially secundum atrial septal or muscular ventricular septal defects

 

 

Hyper-IgE syndrome

 

Triad of eczema, recurrent skin infections, and elevated IgE levels

- pathogenesis due to skewing of TH2 differentiation, which produce increase IL-4, IL-5, and IL-13

- most common form of autosomal dominant hyper-IgE syndrome results from dominant negative mutations STAT3
- shares some features with Wiscott-Aldrich syndrome

 

INI-1 Negative tumors

 

(pediatric) ATRT

Renal medullary carcinoma

Renal rhabdoid tumor (desmin +. keratin +, INI - )

Epithelioid sarcoma

Epithelioid MPNST (1/2)

Extraskeletal myxoid chondrosarcoma (3/20)

Myoepithelial carcinoma (sometimes)

SMARCB1 (INI-1) deficient sinonasal carcinoma

 

 

Juvenile polyposis syndrome

 

AD, SMAD4/DPC4 (18q21), BMPR1A (10q22), and PTEN (10q23)

 

Juvenile polyps of stomach, small and large colon.

- Juvenile polypsois must have: JPs thoughout GI, >5 JPs in colorectum, family hx of JPs

 

Micro: smooth outer contour with erosion, cystically dilated mucus-filled glands, nonadenomatous epithelium, dense nonmuscular collagenous stroma permeated by inflammatory cells

 

Px: ↑ GI cancer, mostly colorectal adenocarcinomas, also stomach, sm intesting and pancreatobiliary

 

Tx: May do prophylactic colectomy.

 

-Note-

Juvenile polyps (in general):  Sporadic, in kiddos <5 yo. 80% in rectum. Not malignant if single

 

Kallmann Syndrome

 

Affects males with hypogonadotropic hypogonadism and anosmia

- most cases C linked and most of these due to mutations in the KAL1 gene on Xp22.3

- isolated growth hormone deficiency

- MC is isolated growth hormone deficiency

 

Kasabach-Merritt syndrome

 

Low platelets due to consuption by Kaposiform Hemangioendothelioma

 

Kearns-Sayre syndrome

 

very uncommon, heteroplasmic, ~4/5 from spontaneous mtDNA rearrangements/deletions, usually 4.9 kb, usually has onset before 20 yo

- very rarely can be maternally inherited

 

pigmentary (salt and pepper) retinopathy, external opthalmoplegia, elevated CSF protein, cerebellar ataxia, cardiac conduction block, sensorineural hearing loss, skeletal myopathy, diabetes mellitus, and hypoparathyroidism

- caused by major structural defect in mtDNA

 

Kasabach-Merritt syndrome

 

death from extensive disease and severe coagulopathy with Kaposiform hemangioendothelioma

 

 

Klinefelter syndrome

 

1:850 live male births

47, XXY males (4/5)

46 XY / 47 XXY mosaicism (1/10)

48 XXYY and others (1/10)

 

Testicular abnormalities - approx 1/10 causes of male sterility 2/2 this syndrome

- renal abnormalities

- gynecomastia

 

 

Klippel-Trenaunay syndrome

 

Condition affection development of blood vessels, ST, and bones

3 features:

1. Port-wine stain

2. abnormal overgrowth of ST and bone (usually in one leg)

3. venous malformations (varicose veins, inc risk of DVT)

 

 

 

Li- Fraumeni syndrome

 

aka Sarcoma, Breast, Leukemia and Adrenal gland (SBLA) syndrome; malignancies occur at an early age

AD TP53 mutations (cr 17p13.1) which normally functions to decide the fate of cells with damaged DNA (can delay cell cycle progression to repair DNA or initiate apoptosis)

- causes inc risk of sarcomas (ie osteosarcoma, adrenal ca., glial tumors of CNS, and wide variety of other tumors)

- median age of onset of ST tumors is 15 yo

 

Dx usually involves 3 close family members having sarcoma b4 age 45 yo

 

Tx in women with breast cancer and Li-Fraumeni should be mastectomy and not lumpectomy 2/2 inc risk of secondary malignancies from radiation

 

Lennox-Gastaut syndrome

 

Pediatric disorder with multiple types of seizures, MR, and abnormal EEG findings

- have worse MR with earlier onset (bwt 1-2 yo), hx of West syndrome, more frequent sx, an identifiable etiology

 

Dx: EEG essential

- can use imaging to look for underlying cause

 

Tx: variety of medical (valproic acid) and surgical (corpus callostomy) tx options

 

 

LEOPARD syndrome

 

AD, mutated protein tyrosine phosphatase, non-receptor type 11 (PTPN11) gene (same as Noonan syndrome)

- described by Gorlin

 

Lentigines

Electrocardiographic conduction abnormalities

Ocular hypertelorism

Pulmonary stenosis

Abnormal genitalia

Retardation of growth

Deafness

Granular cell tumor

 

 

 

Leser-Trelat syndrome

 

sudden dermatologic onset of seborrheic keratosis (look for underlying gastric malignancy)

 

Long QT (LQT) Syndrome

 

Prolonged QT interval prediscposes to ventricular arrhythmia

- QT interval influenced by both acquired and genetic factors

- despite autosomal inheritance, 2:1 female predominance; bc has greater penetrance in females

- genetic factors now categorized by genotype (LQTS1 to LQTS7)

 

LQT1 (KCNQ1) - 11p15.5, encodes a portion of a voltage gated potassium channel, MC mutated gene in LQT syndrome

- exercise (esp swimming) triggered arrhythmias

 

LQT2 (KCNH2, HERG) - 7q35-36, encodes a second voltage activated potassium channel; 2nd MCC LQTS

- auditory stimulus or emotional stimulus triggered arrhythmia

 

LQT3 (SCN5A) - 3p21-25, sleep triggered arrhythmias

 

LQT7 (KCNJ2) - Encodes portions of a channel shared c skeletal muscle; mutations cause Andersen-Tawil syndrome (triad of episodic paralysis, long QT interval, and dysmorphic features)

 

-- (traditional) inherited causes: Romano-Ward syndrome (AD, no hearing loss), Jervell Lange-Nielsen syndrome (AR, with hearing loss), Andersen-Tawil syndrome

-- acquired causes: hypokalemia, hypomagnesemia, hypercalcemia, Medications (tricyclic antidepressants, phenothiazines, macrolide abx, class IA antiarrhthmics, class III antiarrhythmics)

 

Maffucci's syndrome

 

Not familial, PTH1R mutations in some cases, 3p21-22

 

Multiple enchondromas AND soft-tissue (spindle cell) hemangiomas with a 100% malignant transformation rate (risk of developing chondrosarcoma)

- usually in small bones of hands and feet

- is deforming / disabling

 

 

 

Mazabraud's syndrome

 

Not familial, activating GNAS1 mutation, 20q13

 

Polyostic fibrous dysplasia and soft tissue myxomas

 

 

McCloud syndrome

 

Mutated Kx gene on X cr causes weak Kell antigens

- see acanthocytes on PBS

 

 

McCune Albright Syndrome

 

Not familial, mosaicism for mutation in GNAS1 mutation, 20q13

 

***the 3 P's ****

Polyostic fibrous dysplasia (multiple unilateral bone lesions)

Pigmented skin lesions (cafe-au-lait spots)

Precocious Puberty

- and multiple myxomas (ie atrial)?, thyrotoxicosis, Cushing syndrome, pituitary giganticism, breast discharge

- germline mutation incompatible with life

 

Caused by polyzygotic activating mutation on GNAS1 gene (cr 20)

- Gsa permanently turned on, causing crazy protein production

-- is an example of mosaicism

 

Meckel- Gruber syndrome

 

kidney dz, polydactyly, and occipital encephalocele

 

Meigs syndrome

 

Ovarian fibromas, right-sided hydrothorax, ascites (disappears after tumor excision)

 

Miller-Dieker syndrome

 

17p13 microdeletion

- Microcephaly, type 1 lissencephaly, heart malformations, renal malformations, seizures, prominent forehead, vertical furrowing of brow

 

 

Pearson syndrome

 

AD pancreatitis (pancreatic exocrine insufficiency) and marrow failure

- chromosomal breakage syndrome affecting the mitochondrial DNA

- marrow shows sideroblastic anemia with vacuolization of precursors

- the molecular defect is a microdeletion within the mitochondrial DNA

 

 

Peutz-Jeghers syndrome

 

aka Hereditary intestinal polyposis syndrome

 

Autosomal dominant; STK11/LKB1, 19p13 – tumor suppressor gene, >9/10 get malignancy over lifetime

 

Harmartomatous polyp (mostly sm. bowel – usually jejunum)

Micro: Lined by mucinous mucosa with arborizing thin complexly branching muscle bundles

Cancers of GI tract, pancreas, breast and bladder

 

Mucocutaneous Hyperpigmentation: Dark blue or brown macules around the mouth, eyes, nose and peri-anal area

 

Sex cord tumor with annular tubules (SCTAT), ovary

Large cell calcifying Sertoli cell tumor, testicle

 

Adenoma Malignum: The neoplastic glands are lined by mucin-producing, columnar cells with basally located nuclei. The glands are variable in shape and size and surrounded by desmoplastic response

 

Inc risk of breast, GI, pancreas, bladder ca

Pierson syndrome

 

B2 laminin, encoded by LAMB2 [3p21]

- B2 laminin is a component of the glomerular basement membrane

- associated with microcoria (fixed, narrow pupils)

- death within several months

- renal biopsy shows mesangial sclerosis and crescents

 

POEMS syndrome

 

Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes (glomeruloid hemangioma)

 

Polycystic Ovarian Syndrome (PCOS)

 

see Stein-Leventhal syndrome

 

Prader-Willi

 

Paternal 15q11.2 microdeletion

- hyperphagia, obesity, hypogonadism, mild MR

 

 

Reed syndrome

 

AD; fumarate hydratase mutation

Multiple piloleiomyomas assoc c papillary RCC and uterine leiomyomas

 

 

Retinoblastoma (RB)

 

• Tumor suppressor gene, 13q14, 4/10 inherited

• Rb binds to E2F and prevents cells entering S phase

• E2F enhances transcription of c-myc and c-fos genes by binding to the promoters

• E7 protein binds to Rb protein, preventing its association with E2F

• E6 binds p53 protein, targeting it for destruction by proteasomes

 

- bilateral retinoblastomas, pineoblastomas, inc risk osteosarcoma

 

 

Rhabdoid Tumor Predisposition Syndrome (RTPS)

 

Germline inactivation of 1 allele of a gene occurs

- when mutation occurs in SMARCB1 gene, syndrome called RTPS1 and when mutation is in SMARCA4 gene is called RTPS2

- children c RTPS develop tumors at a younger age

- adults c the mutation get multiple schwannomas

 

Rombo syndrome

 

Trichoepitheliomas, milia, hypertrichosis, BCC, atrophoderma, vasodilation and cyanosis

 

Rotor Syndrome

 

AR; multiple defects in hepatocellular uptake and excretion of bilirubin pigments

 

Sx: asymptomatic conjugated hyperbilirubinemia, jaundice, normal lives; liver looks normal

 

Ruvalcaba-Myhre-Smith syndrome

 

- aka Bannayan-Ruvalcaba-Riley syndrome, Riley-Smith syndrome

 

Rare genetic condition c macrocephaly, developmental delay, multiple noncancerous tumors and tumoroid-growths like hamartomas and dark freckles on penis

- shares features c Cowden syndrome

 

Genes: PTEN mutations (60%)

 

Schwachman-Diamond syndrome

 

A pancreatic lipomatosis syndrome with marrow failure and exocrine pancreatic insufficiency

- the pancreas demonstrates fatty metamorphosis; pancreatic islets are preserved

- mutations in SBDS (Shwachman-Bodian-Diamond syndrome)

 

 

Small round blue cell tumors

 

Kiddos

Neuroblastoma (+ SYN, neg CD99)

Wilms tumor (blastema-predominant) (+ CK/ET1, desmin)

PNET/ Ewing sarcoma (+ CD99, NSE/SYN, PAS)

Medulloblastoma (+ SYN, variable GFAP)

Rhabdomyosarcoma (solid type)

Small cell osteosarcoma (variable CD99, osteocalcin +)

Lymphoblastic lymphoma (+ CD45, CD99)

Poorly differentiated synovial sarcoma

 

Adults

Lymphoma (+CD45, other lymphoid markers)

Small cell carcinoma (+ CK/EMA, NE markers, var TTF)

Merkel cell ca (+CK/EMA, NE markers, NF, Merkel cell polyomavir

Desmoplastic small round cell tumor (+ CK/EMA, NSE, TTF, desmin [neg actin])

Mesenchymal chondrosarcoma (+SOX-9, S100, CD99)

Small cell melanoma

Epithelioid GIST

Malignant glomus tumor

Sclerosing epithelioid fibrosarcoma

Midline NUT carcinoma

 

Smith-Lemli-Opitz syndrome (SLOS)

 

AR, inborn error of cholesterol synth, mutation in enzyme 7-Dehydrocholesterol reductase (DCHR7) causing hypocholesterolemia; missense mutations account for 87.6 of SLOS cases

- pts given severity score based on levels of cerebral, ocular, oral and genital defects

- MC facial features are microcephaly, bitemporal narrowing, ptosis, short and upturned nose, micrognathia, epicanthal folds, capillary hemangiomas of the nose

- can also have low-set and posteriorly rotated ears, high-arched, narrow hard palate, cleft lip, agenesis of the corpus callosum, cerebellar hypoplasia, inc ventricular size, polydactyly / syndactyly, ambiguous genitalia, congenital heart defects, renal, pulmonary and eye abnormalities

- simvastatin is an inhibitor of HMG-CoA reductase and has been known to treat SLOS

 

Smith-Magenis syndrome

 

17p11.2 microdeletion

Moderate MR, prominent forehead, flat broad midface, self-multilating behavior, disturbed REM sleep

 

Stein-Leventhal syndrome

 

aka Polycystic ovarian syndrome (PCOS) or hyperandrogenic anovulation

Seen in women 18-44 yrs

Sx: anovulation, menorrhagia (heavy menstrual bleeding), hirsutism, infertility, acne, acanthosis nigricans

 

Due to obesity and inactivity

- can dx if: 1) anovulation, 2) hyperandrogenemia, 3) ovarian cysts

 

Assoc dz's: DM2, obesity, sleep anea, heart disease, mood disorders, endometrial ca,

 

 

Stiff Person Syndrome (SPS)

 

Autoimmune process that coexists c type I DM and other autoimmune dz's such as vitiligo, thyroiditis, and pernicious anemia

 

 

Sturge-Weber Disease

- aka Encephalotrigeminal Angiomatosis

 

No known genetic / protein defects, not inherited / familial?

 

• Encephalotrigeminal angiomatosis

• Unilateral lesions, no familial predisposition

• Facial port wine stain/Nevus flammeus of face, especially trigeminal nerve region

• Ipsilateral leptomeningeal venous angiomas

• Calcification of superficial cortex, underlying angioma, “tram tracks”

• Hemihypertrophy of skull

• Cortical atrophy, hemiparesis, contralateral hemiatrophy of body

• Seizures, retardation

- pheochromocytomas

 

 

 

Tuberous Sclerosis

- aka Bourneville syndrome

 

AD

TSC1, 9q34, hamartin

TSC2 (MC) 16p13.3, tuberin

- TSC2 expression leads to inc mTOR activity

 

IHC: (+) HMB45

 

-Subependymal giant cell astrocytomas (SEGA)

- cardiac rhabdomyomas

- PEComas (perivascular epithelioid cell tumors): renal angiomyolipomas (2/10), clear cell "sugar" tumors, pulmonary lymphangioleiomyomatosis (lung dz of younger women that have melanocytic and sm muscle cell markers)

-Tubers (cortical and subependymal glioneuronal hamartomas)

- rectal microhamartomatous polyps

- dermal angiofibromas (adenoma sebaceum) of face, subungual fibroma, ash-leaf patches

*** Zits, Fits, and Nit-Wits**

- zits are the angiofibromas, fits are seizures and nit-wits from low inttelligence

 

***TRASH SMASHAR ***

Tuberin (regulates protein translation and cell growth)

Rhabdomyomas cardiacas - nearly 100% specific for TS

Angiomyolipomas in kidney that cause flank pain (2/10)

Subependymal GC astrocytoma: "candlestick dripping" in ventricles

Hamartomas (tubers) in cortex

 

Seizures (infantile spasms)

Mitral regurg

Ash-leaf spots (hyperpigmented skin lesions)

Shagreen patches - rough papules c orange peel consistence c Wood's lamp

Hamartin (regulates neuronal synapse formation) and tuberin heterodimers

Adenoma sebacum - red brown papules on nose and cheeks c butterfly pattern, which are really angiofibromas

Rapamycin (sirolimus) decreases seizure freq and subepi GC size

 

 

Turcot syndrome

 

Type 1

- Germline mutations of hMLH1, hMSH2 or hPMS2

- Glioblastoma multiforme, colorectal carcinoma

 

Type 2

- Germline mutation of APC gene

- Medulloblastoma, FAP

 

 

Turner syndrome

 

45 XO, 1/3000 female births, neck (nuchal) webbing, wide-spaced nipples (shield chest), short stature, streak ovaries, cardiac anomalies in 1/2 of cases, bicuspid aortic valve is MC defect, then coarctation of the aorta. Aortic root dilation is common and may lead to aortic dissection

- single umbilical artery

assoc c ganglioneuromas and gonadoblastomas

 

VATER / VACTERL Syndrome

 

Vertebral anomalies, Anal atresia, Tracheal-Esophageal fistula, Renal and Radial defects (VATER), also known as Vertebral anomalies, Anal atresia, Cardiac defects, Tracheal-Esophageal fistula, Esophageal atresia, Renal and Radial defects, Limb defects (VACTERL) syndrome

- caused by undefined defects in development of embryonic mesoderm

- unknown etiology, probably multifactorial

- liver can show absent/atrophic portal veins c inc prominent arterioles in portal tracts

- liver findings similar to Abernethy syndrome (focal nodular hyperplasia)

 

von Hippel-Lindau

 

AD familial ca syndrome

vHL tumor gene suppressed on 3p25-26, involved in ubiquination

 

CNS hemangioblastoma (Lindau's tumor in cerebellum) / cavernous hemangioma, retinal angiomas, renal cysts, RCC (clear cell type), pancreatic cysts, pancreatic serous cystadenoma, islet cell tumors, epididymal/ovarian papillary cystadenoma(1/3 of males, can be Pax2+), endolymphatic sac tumor in ear (Heffner tumor), Adnexal Papillary Cystadenoma of Probable Mesonephric Origin (APMO, 8/8), Epididymal cystadenomas

 

 

 

WAGR syndrome

 

Germline 11p13 deletion (not familial), involving PAX6 gene (aniridia) + WT1 gene

 

- Wilms tumor, Aniridia, Genitourinary anomalies, Retardation (mental)

 

 

Weber-Christian disease

aka Idiopathic relapsing febrile non-suppurative panniculitis

 

Rare dz of middle-aged females c recurring inflammation of fat what can form subq nodules which heal c depression on overlying skin

- form of panniculitis

 

WHIM Syndrome

 

Warts, hypogammaglobulinemia, infx. myelokathexis (retention of neutrophils in BM stroma) -- neuts only

- associated with CXCR4 mutations (seen in LPL)

 

William syndrome

 

elastin gene, 7q11.23 microdeletion

- dysmorphic (elf-like) facial features, abnormal dentition, MR, short stature, hypercalcemia, abnormalities of CT (hernias, diverticula, joint laxity, skin laxity) and structural cardiac and vascular defects

- most distictive cardiac anomaly is supravalvar aortic stenosis (hourglass stenosis)

 

Wiscott Aldrich syndrome

 

X-linked, WASP gene defect

 

- Thrombocytopenia, infection, eczema

- Small granulated PLT, no δ granules EM

- ↑ IgE and IgA, ↓ IgM and IgG

- T cells present but ↓ response to mitogens

- ↑ Malignancy

 

Wolf syndrome

 

4p deletion

- IUGR, heart malformation, microcephaly, cleft lip and palate, broad nasal root, severe MR

 

Zellweger Syndrome

 

One of a group of 4 related dz's called peroxisome biogenesis disorders (PBD), caused by defects in 1 of 13 PEX genes needed for normal function of PEX genes

- needed for normal brain development and help form myelin

- have hepatomegaly, high forehead, underdeveloped eyebrow ridges, wide-set eyes, neurologic abnormalities (seizures), lack muscle tone

- px is poor

 

Zollinger-Ellison Syndrome

 

Gastroma causes hypergastrinemia leading to inc acid secretions and severe Peptic Ulcer Disease (PUD)

 

Gross: very hypertrophied rugae in body and fundus, atrophic antrum

 

Micro: inc parietal cells, dec foveolar

 

 

Tumor Suppressor Genes

• RB  13q14

• P53  17p13

• APC 5q21

• VHL 3p25

• NF-1 17q11

• NF-2  22q12

• P16  9p21

• WT1 11p13

• PTEN 10q23

• BRCA1 17q21

• BRCA2 13q12

• ATM 11q22

• DCC  18q21

 

 

Oncogenes

• HER2/Neu

• c-Kit

• PDGFRA

• RAS

• ABL

• ERB-B (EGFR)

• MYC (C, N, L)

• RET