Tag Archives: Syndrome

Sturge Weber Syndrome

Sturge Weber Syndrome

- skin and brain angiomas
- in trigeminal nerve distribution

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Juvenile Polyposis Syndrome

Juvenile Polyposis Syndrome

Inheritance: sporadic or autosomal dominant
often mutations in PTEN or smad4/dpc4

Diagnosis criteria:
a) >5 colorectal juvenile polyps
b) juvenile polyps in entire GI tract
c) any polyps in a patient with a family history of Juvenile Polyposis Syndrome

Gross: peduculated polyp

Histology

- eroded surface with reactive and regenerative epithelium
- cystically-dilated glands
- prominent stroma with a mixed inflammatory infiltrate

Genetics: SMAD4, BMDR1A mutation

Associations: adenomas, cancers of the stomach to colon and pancreas

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Zollinger Ellison Syndrome

Zollinger Ellison Syndrome

Gastrinoma

Pathophysiology:

- gastrin-secreting endocrine tumor in pancreas (gastrinoma) or in ectopic gastric tissue (duodenum or Meckel’s diverticulum)

- causes hypergastrinemia and an increase in serum gastrin

- 20% associated with MEN-1, 80% sporadic

Gross Appearance and Location:

- fundus and body (where parietal cells are)

- massive rugal folds

Histology:

- increase in parietal cells and hypertrophy of the fundus and body of the stomach

- enterochromaffin-like cell linear hyperplasia in body of stomach

Immunohistochemistry:

- gastrinoma is chromogranin, synaptophysin and gastrin positive

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Fragile X Syndrome

Fragile X Syndrome

- second most common cause of MR

- X-linked disorder

What is the nucleotide repeat sequence?

-trinucleotide expansion of FMR gene of “CGG”

What are the clinical features?

- long face, big ears,

What is Sherman’s paradox?

- risk of MR higher in grandson than the brother of the transmitting male. Because the premutation is amplified to a mutation during oogenesis → resulting in all males with MR and 50% of females.

What is anticipation?

-mutation gets worse with each generation.

What is the difference between premutations and mutations?

- premutations: normal transmitting males and carrier females

- mutations (>230 repeats) → results inactivation of FMR1

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Familial Adenomatous Polyposis Syndrome

Familial Adenomatous Polyposis (FAP) Syndrome

Familial Adenomatous Polyposis Syndrome Inheritance pattern

- autosomal dominant inheritance

- APC gene is on chromosome 5q21
- APC gene plays a role in the WNT pathway in the degradation of the beta-catenin

- beta-catenin role is to turn on transcription factors in the nucleus that lead to cell cycle progression
-mutations in the APC leads to absence of b-catenin degradation and signal independent tranlocation into the nucleus where it turns on the cell cycl

Familial Adenomatous Polyposis Syndrome Clinical Presentation

- two types of clinical presentations:

Classic Familial Adenomatous Polyposis

- minimum of 100 colonic polyps

- polyps in ampulla of Vater – this leads to a prophylactic colectomy in siblings and first-degree relatives which are at risk

Attenuated Familial Adenomatous Polyposis

- patients tend to develop fewer polyps (average 30), and most of the polyps are located in the proximal colon

- lifetime risk of cancer development is usually around 50%

Gardner syndrome

- polyps identical to those in classic FAP
- multiple osteomas (particularly of the mandible, skull, and long bones)
- epidermal cysts
- fibromatosis – desmoid tumors
- less frequent are abnormalities of dentition, such as unerupted and supernumerary teeth
- higher frequency of duodenal and thyroid cancer

Turcot syndrome

- combination of adenomatous colonic polyposis and tumors of the CNS
2/3 have  have APC gene mutations and develop brain medulloblastomas

- 1/3 have mutations in one of the genes associated with HNPCC and develop brain glioblastomas

Gross Features of Familial Adenomatous Polyposis

-hundreds to thousands of adenomas evenly distributed through colorectum  and appendix
- adenomas range from microscopic to 1cm in diameter with larger adenomas found in the rectosigmoid
- rectum occasionally spared, especially in the attenuated FAP
- colorectal carcinomas may be multifocal

Microscopic Features of Familial Adenomatous Polyposis

- histologically identical to sporadic adenomas
- normal intervening mucosa

- adenomas evolve from single adenomatous crypts

Symptoms and Management

- patients may be asymptomatic before puberty
- initial symptoms are  rectal bleeding and diarrhea
- carcinomas start about 6 years after first symptoms
- 100%  colon cancer without intervention
- treatment is prophylactic total colectomy
- following colectomy, the most common cause of death is periampullary cancer in 20%

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Hereditary Nonpolyposis Colorectal Cancer Syndrome


Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome

 

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome, also known as Lynch syndrome, is a rare colorectal syndrome that can lead to cancer of the colon.

Hereditary Nonpolyposis Colorectal Cancer Syndrome Inheritance pattern
- autosomal dominant
- syndromal patients have only one functional allele and cancer occurs through loss of heterozygosity (LOH)
- mutations occur in mismatch repair genes (MLH1, MSH 2, MSH6, PMS 1, PMS 2)
- mutations lead to microsatellite instability which are mostly repeats in intronic regions

What to look for?

- you can look for the loss of the genes themselves

- you can look at particular microsatellite loci and see how many have instability
- 0/5 – stable
- 1/5 – low frequency instability
- 2 or greater/5  – high frequency of instability – MSI-H
- microsatellite instability is NOT specific to HNPCC, as it is seen in 10-15 % of sporadic colorectal carcinomas. Sporadic tumors arise in older patients who lack a family history. The activity of the mismatch repair genes in sporadic tumors is lost through hypermethylation

Diagnostic criteria is through the Amsterdam II criteria

Clinical presentation

- development of multiple cancers at an early age, including cancer of the colon, endometrium, renal pelvis and ureter, small bowel, ovary, brain, hepatobiliary tract and sebaceous tumors 

Muir -Torre Syndrome

- sebaceous tumors along with HNPCC type of internal malignancy

Turcot Syndrome

- tumors of the CNS (usually gliobalstomas) and multiple colorectal tumors

Gross Appearance

- predilection for right colon and cecum all the way to the transverse colon
- usually polypoid in appearnace rather than diffuse

 

Microscopic Appearance

- sporadic tumors have the same features as tumors associated with HNPCC

- proximally located mucinous type of colorectal adenocarcinomas +/- tumor infiltrating lymphocytes

- proximally located, poorly differentiated medullary or undifferentiated colorectal adenocarcinomas – these are well circumscribed and lacking abundant desmoplastic stroma and may contain tumor infiltrating lymphocytes

- adenomas – many have a villous morphology and high grade dysplasia, with rapid progression to carcinoma

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Carcinoid syndrome

Carcinoid syndrome

Symptoms of Carcinoid Syndrome

- skin flushing
- diarrhea

- right sided heart disease due to fibrosis of the tricuspid valve and stenosis of the pulmonary valve

- bronchoconstriction

Detection of Carcinoid Syndrome

Serotonin secretion is confirmed  by measuring the 24 hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), which is a breakdown product of the hormone, serotonin.

Management of Carcinoid Tumors

Low risk Carcinoid

Local excision for small lesions < 2 cm, with no mesoappendix invasion and no lymphovascular invasion.

Uncertain behavior if > 2 cm or lymphovascular invasion, no mesoappendix invasion.

High risk lesions have at least a cecal resection. These high risk tumors are found at the base of the appendix with caecal margin involvement.

Higher risk lesions require hemicolectomy. These include carcinoid lesions above 2 cm or with invasion of mesoappendix.

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