Syndromes Flashcards
Familial retinoblastoma
Ch 13
Familial adenomatous polyposis
aka familial polyposis coli
5q21
can have desmoid tumors (aggressive fibromatosis)
MEN 1
11p13 (MEN1 tumor suppressor gene)
autosomal dominant
aka Werner syndrome
3 P’s (parathyroid, pancreas, pituitary)
- primary hyperparathyroidism (hypercalcemia –> kidney stones) - hyperplasia or adenomas
- pancreatic microadenomas, gastrinomas (Zollinger-Ellison syndrome), insulinomas
- pituitary adenomas (esp prolactinoma)
- other: duodenal gastrinomas (> pancreatic), carcinoid tumors, thyroid and adrenocortical adenomas, lipomas, thyroid C-cell hyperplasia
MEN 2
RET proto-oncogene (10q12)
MEN 2A (Sipple Syndrome):
- pheochromocytoma (40-50%, bilat, extra-adrenal)
- medullary thyroid carcinoma (100%)
- primary hyperparathyroidism (10-20%)
MEN 2B (aka MEN-3)
- medullary thyroid carcinoma (multifocal, more aggressive than in MEN-2A)
- pheochromocytomas
- neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract
- marfanoid habitus
Familial medullary thyroid cancer
- variant of MEN-2A w/ strong predisposition to medullary thyroid cancer (older age, more indolent) but not the other clinical manifestations of MEN-2A or MEN-2B. A substantial majority of cases of medullary thyroid cancer are sporadic, but as many as 20% may be familial.
* prophylactic thyroidectomy
Neurofibromatosis
NF 1 (von Recklinghausen neurofibomatosis)
- neurofibromin gene (ch 17)
- autosomal dominant
- cafe-au-lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macrocephaly, short stature and mental retardation
NF 2 (MISME Syndrome”, for “Multiple Inherited Schwannomas, Meningiomas, and Ependymomas”)
- Merlin (schwannomin) gene 22q11
- bilateral vestibular schwannomas, tumors of other cranial nerves/meninges, tumors of spinal cord (intramedullary - astrocytomas & ependymomas; extramedullary - schannomas & meningiomas), juvenile subcapsular cataracts
Von Hippel-Lindau disease
VHL tumor suppressor gene (3p25-26)
- autosomal dominant
- retinal and CNS hemangioblastomas
- retinal angiomatosis –> retinal detachment
- pheochromocytomas
- multiple cysts in pancreas and kidneys
- clear cell renal cell carcinoma
- pancreatic neuroendocrine tumors
- endolymphatic sac tumors
- epididymal papillary cystadenomas
- cafe-au-lait spots
Turcot’s syndrom
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- aka brain tumor-polyposis syndrome or glioma-polyposis syndrome
- autosomal recessive (FAP with brain tumors)
- HNPCC genes (DNA mismatch/repair defect)
- coexistence of a hereditary colon cancer syndrome (like FAP or HNPCC) and CNS tumors
- FAP - medulloblastoma > astrocytoma > ependymoma
- HNPCC - GBM
DNA Repair Defect Syndromes
- Xeroderma pigmentosa - 9, 19, 11, 16, 13
- Ataxia-telangiectasia - 11q22.3
- Bloom’s syndrome - 15q26.1
- Fanconi’s anemia - 9, 16, 3, 6
* all are autosomal recessive
xeroderma pigmentosum
- autosomal recessive d/o of defective DNA repair (nucleotide excision repair)
- 7 repair genes (XPA-XPG)
- inc risk of skin cancer (melanoma, SCCa, BCCa, fibrosarcoma) after UV light exposure (UV radiation –> crosslinking of pyrimidine residues, preventing normal DNA replication)
- 9q22 and others (19, 11, 16, 13)
Ataxia-telangiectasia
- aka Louis-Bar syndrome
- defect in ATM(ataxia-telangiectasia mutated) gene - 11q22
- autosomal recessive d/o of defective DNA repair
- Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX are tumor suppressors.
- neurodegenerative (progressive cerebellar ataxia)
- mucocutaneous telangiectasias (on sclerae and skin)
- recurrent upper resp tract (sinopuulmonary) infxn
- inc risk CANCER (esp leukemia/lymphoma, pancreatic ductal adenoca, )
- impaired organ maturation, increase x-ray sensitivity
Bloom’s syndrome
- aka congenital telangiectatic erythema
- autosomal recessive d/o of defective DNA repair
- telangiectases and photosensitivity, growth deficiency of prenatal onset, variable degrees of immunodeficiency, and increased susceptibility to neoplasms of many sites
- mutation in BLM gene - 15q26.1 - a DNA helicase that participates in DNA repair by homologous recombination
- Increased sister chromatid exchanges and chromosomal instability also occur, which is assumed to be responsible for the phenotype and the cancer predisposition
- growth delay
- cancer risk 150-300x general pop
- 20% develop malignancies (eg, acute myeloid leukemia, lymphoma, gastrointestinal adenocarcinoma)
- decreased immunoglobulin A and immunoglobulin M, with recurrent respiratory and gastrointestinal tract infections
- bird-like facies, short stature
Fanconi’s anemia
- autosomal recessive d/o of defective DNA repair
- 15 diff genes (FANCB is X-linked recessive, the rest are AR) - chromosomes 9, 16, 3, 6
- most frequently reported of the rare inherited bone marrow failure syndromes
- hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors, and other cancers.
- birth defects (dangling thumbs, facies, dislocated hips), kidney and heart defects
- aplastic anemia, MDS, AML, head and neck squamous cell carcinoma (HNSCC), liver tumors (adenomas and hepatomas; primarily but not exclusively in patients who had aplastic anemia that was treated with oral androgens), vaginal squamous cell carcinoma (SCC), and brain tumors
Denys-Drash syndrome
- gonadal dysgenesis
- nephropathy
- Wilms tumorz
The cause of DDS is most commonly (96% of patients) an abnormality in the WT1 gene
The presenting characteristics of DDS include loss of playfulness, decreased appetite, weight loss, growth delay, abnormal skeletal development, insomnia, abdominal pain, constipation, and anuria.
Clinically, Denys–Drash is characterized by the triad of pseudohermaphroditism, mesangial renal sclerosis, and Wilms tumor. The condition first manifests as early nephrotic syndrome and progresses to mesangial renal sclerosis and ultimately renal failure, usually within the first three years of life.
Li-Fraumeni syndrome
- rare autosomal dominant hereditary disorder.
- also known as the Sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.
- persons with Li–Fraumeni syndrome have an approximately 25-fold increased risk of developing a malignant tumor by age 50 than the population average, and are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma
Cushing’s syndrome
high ACTH, adrenal cortical adenomas
can get small cell lung cancer
Pt with adrenal cortical adenoma, excess aldosterone (hypernatriemia, hypokalemia, HTN)
Conn’s syndrome
Patient with tumor and hypoglycemia
fibrosarcoma, solitary fibrous tumor, HCC, insulinoma
overproduction of insulin or insulin-like growth factors
Pt has tumor and is polycythemic
renal cell carcinoma
cerebellar hemangioblastoma
HCC
leiomyoma
solitary fibrous tumor
acanthosis nigrans
predispostion to gastric carcinoma, lung carcinoma, uterine carcinoma
Pt with skin lesions and acoustic neuromas
NF-2!
Pt with rhabdomyoma or angiomyolipoma
Tuberous sclerosis
ch 9 & 16
cortical tubers, sclerosis, SEGAs (subependymal giant cell astrocytoma), cardiac rhabdomyomas, pulm LLM (lymphangioleiomyomatosis), AMLs, sebaceous adenomas, ash green patches, subungual fibromas
Pt with cavernous hemangioma and renal cell carcinoma
von Hippel Lindau
3p25
RCC (bilateral), papillary cystadenoma of pancreas, pheos, cavernous hemangiomas/hemangioblastomas of retaina/cerebellum/brainstem, hemangiomas/cysts of pancreas, skin, liver, kidney
Gardner’s syndrome
colonic adenomas, osteomas, desmoplastic fibromas, fibromatosis
loss of regulation
FAP & jaw osteomas
desmoids, cysts of skin, soft tissue tumors (desmoplastic fibromas)
papillary thyroid carcinoma (according to endocrine osler notes)
Inactivation of APC tumor supressor gene in Gardner or sporadic fibromatosis
leads to accumulation of nuclear beta-catenin
Cowden syndrome
aka multiple hamartoma syndrome
mutation of PTEN gene on 10q23 (same as MEN II, MEN1 11p13)
9q22.3
hamartomatous neoplasms of skin, mucosa, GI/GU tracts, CNS, bones
Trichelemmomas ,oral mucosal papillomatosis, acral and palmoplantar keratoses, increased risk of thyroid and breast cancer (> colon and renal cell carcinoma)
thyroid adenomatoid nodules and follicular neoplasms (according to osler endocrine notes)
Peutz-Jeghers syndrome
mutation in STK11 gene on chromosome 19
hamatomatous polyps (esp small bowel) and oral mucocutaneous pigmentation
women: SCTATs (sex cord tumors with annular tubules), adenoma malignum of cervix
- men: large cell calcifying sertoli cell tumors
inc risk: breast, lung, ovary, pancreas and uterine Ca; rare malignant tranmsformaion in GI tract
mnemonic “PASS Boards”: Pancreas, Adenoma malignum of cervix, Sex cord tumors, Sertoli tumors, Breast
Cronkite-Canada syndrome
non-inherited
FAP (hamartomatous polyp[s) with skin and nail changes
Fabry’s disease
- X-linked recessive sphingolipidosis
- deficiency of alpha-galactosidase A
- angiokeratomas, renal insufficiency, cardiac failure
- vacuolated myocytes
- EM: intralysosomal dense lamellae (zebra bodies)
Carney’s syndrome/complex
- cutaneous & cardiac myxomas (myxoid FAs)
- spotty skin pigmentation (lentigines & blue nevi)
- Endocrine overactivity &/or tumors (adrenal, testicular, thyroid, pituitary - acromegaly, hypercortisolemia, sexual precocity)
- large cell calcifying Sertoli cell tumor
Carney’s triad
- Multiple Pulmonary chondromas (hamartomas)
- extra-adrenal_ P_aragangliomas
- GISTs of the stomach
- Think: Peter, Paul, and Gary
- nonfamilial