191. Genetic Syndromes Flashcards by Michael Peabody

Neuroendocrine tumor of the C-cells of the thyroid gland

All MEN 2 patients will develop __

MEN2A incidence peaks in 3rd decade of life
MEN2B occurs earlier and is more aggressive

75% of cases are sporadic, but will have __ mutation

Early thyroidectomy is important

MTC

RET

How well did you know this?

Not at all

Perfectly

Classic triad of symptoms with paragangliomas/pheochromocytomas

Half of patients will have paroxysmal hypertension as well

Episodic headache
Sweating
Tachycardia

How well did you know this?

Not at all

Perfectly

AD syndrome with a two-hit model in a tumor suppressor gene

Clinical features:

hemangioblastomas of the brain
retinal capillary hemangioblastomas
clear cell renal carcinomas
pheochromocytomas
endolymphatic tumors of the middle ear
neuroendocrine tumors of the pancreas
papillary cystadenomas of the epididymis and broad ligament

Von Hippel-Lindau

Mutations in the VHL gene

How well did you know this?

Not at all

Perfectly

Most common genotype is 45 XO, but may have a partial monosomy
- may be mosaic genotype

Turner Syndrome

How well did you know this?

Not at all

Perfectly

90-95% of cases

Medullary Thyroid cancer (90-100% of cases)
- presents later compared to its cohort

Primary Hyperparathyroidism (0-20%)

Pheochromocytomas (0-50%)

Extra-endocrine manifestations:

Hirschsprung’s disease
Cutaneous lichen amyloidosis

MEN2A

How well did you know this?

Not at all

Perfectly

Genetic defect causing abnormal insulin secretion and a low renal threshold for glucose
- defect in hepatocyte nuclear factor-1-alpha

Risk of microvascular disease

Treated with sulfonylureas

Type 3 MODY

How well did you know this?

Not at all

Perfectly

Designates the fact that an identical or highly similar phenotype may result from mutations in different genes

Locus heterogeneity

How well did you know this?

Not at all

Perfectly

Presents as:

increased length of the arms and legs
gynecomastia
psychosocial abnormality
inattention
impairment of linguistic function
small, firm testes with low sperm count and infertility = hypogonadism

Higher risk of insulin resistance and Type 2 DM

Klinefelter’s Syndrome

How well did you know this?

Not at all

Perfectly

Classic virilizing CAH in __:

- ambiguous genitalia at birth due to excess androgens in utero

Females

How well did you know this?

Not at all

Perfectly

Catecholamine-producing tumor in the adrenal medulla

Pheochromocytoma

How well did you know this?

Not at all

Perfectly

Germline mutation in TK2 (intracellular domain) of RET proto-oncogene leads to

MEN2B

How well did you know this?

Not at all

Perfectly

In monozygotic twins where on twin has type 2 DM, there is __% chance the other twin develops type 2 DM

How well did you know this?

Not at all

Perfectly

Most common types of MODY? (2 of them)

Type 2 and Type 3

How well did you know this?

Not at all

Perfectly

Hyperfunctioning endocrinopathies 2/2 to disease:

gonadotropin-independent precocious puberty
hyperthyroidism
GH excess
hyperprolactinemia
hypercorticolism

Non-endocrine manifestations:

heart disease
renal phosphate wasting
hepatobiliary dysfunction

McCune-Albright Syndrome

How well did you know this?

Not at all

Perfectly

MEN
Von Hippel Lindau
Li Fraumeni
Pheochromocytoma/Paraganglioma Syndromes

Endocrine Tumor Syndromes

How well did you know this?

Not at all

Perfectly

Indicates that different mutations in the same gene can cause an identical or similar phenotype

Allelic heterogeneity

How well did you know this?

Not at all

Perfectly

Most __ are lethal during early fetal development

Monosomies

How well did you know this?

Not at all

Perfectly

Most common pancreatic/duodenal tumor of MEN1
- also found in Zollinger-Ellison Syndrome

Also, other tumors seen in this region are

insulinomas
non-functioning tumors
carcinoid/VIPomas/glucagonomas

Gastrinomas

How well did you know this?

Not at all

Perfectly

Genetic defect in glucokinase which alters cells’ abilities to sense glucose
- increased plasma levels of glucose

No risk of microvascular disease typically

Treat w/ diet modification

Type 2 MODY

MEN2 is an AD gain of function mutation of __ proto-oncogene

RET

Classic manifestations = 3 Ps

parathyroid
pancreas
pituitary

MEN 1

Autoimmune Polyglandular Syndromes are d/t mutation in the __ gene
- modulates the transcription of peripheral self-antigens in the thymus rpesented by HLA molecules to maturing T cells

APS1, APS2, APS3, APS4
- associated with other autoimmune diseases

AIRE

5-10% of cases

Medullary Thyroid Carcinoma (100%)
- presents earlier and tends to be more aggressive compared to its cohort

Pheochromocytoma

Intestinal ganglioneuromas

Specific Phenotype

MEN2B

Classic virilizing CAH in __:
- Age 1-4 weeks suffers from adrenal insufficiency with failure to thrive, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, shock

Males

Single gene defect leading to the development of DM - AD mode of transmission Often misdiagnosed as type 2 DM - lack of diabetes autoantibodies (so not type 1 either)

Monogenic Diabetes (MODY)

Presents as: - Small ovaries with few or no follicles, STREAK GONADS leading to infertility - short stature - swelling of hands and feet - shield chest - webbed neck - low set hairline - heart disease - coarctation of aorta - horseshoe kidney - ear infections and hearing loss - ADHD - non-verbal learning disability Higher risk of autoimmune conditions Require estrogen-replacement therapy

Turner Syndrome

What do you treat classic virilizing CAH with?

Hydrocortisone and salt supplementation

AD inactivation of PRKAR1A Endocrine manifestations: - adrenocortical tumors - primary pigmented nodular adrenocortical disease leads to Cushing's Syndrome - thyroid nodules - pituitary adenomas - large cell calcifying sertoli cell tumor of the testicles - ovarian cysts or teratomas Non-endocrine manifestations: - Skin: cafe au lait spots, myxomas, blue nevi, lentigines - Eyes: pigmented lesions of conjunctiva and palpebra - cardiac myxomas - nerve sheath tumors - breast myxomas - osteochrondromyxoma - rarely: uterine myxoma, hepatocellular myxoma, pancreatic neoplasms

Carney complex

Extraadrenal tumor on sympathetic or parasympathetic ganglia - can be secretory (abdominal) or non-functional (head and neck)

Paraganglioma

Most common manifestation of MEN 1 - presents in 2nd-4th decade of life - generally needs treatment with 3.5 gland resection

Primary hyperparathyroidism

Mutated protein in MEN1 Undergoes "two hit" hypothesis

Menin

AD mutation in the tumor protein p53 - damaged DNA can survive and proliferate Clinical manifestations: - sarcoma - premenopausal breast cancer - brain tumors: gliomas and medulloblastoma - adrenocortical tumors

Li Fraumeni Syndrome

Marfinoid Habitus with scoliosis High-arched palate Megacolon Neuromas on tongue, mouth, and eyelid

MEN2B (specific phenotype)

__ mutations that lead to disease are more likely to manifest in adulthood, unlike chromosomal and monogenic diseases that appear after birth-prepuberty

Polygenic

Germline mutation (intracellular and extracellular) of RET proto-oncogene leads to

Familial MTC

Most common cause of male hypogonadism (1:1000 males in US) Most common genotype is 47 XXY - due to non-disjunction of sex chromosomes - Can be mosaic

Klinefelter's Syndrome

Examines the protein instead of the gene | - ex: looking for adrenal intermediates for CAH

Biochemical testing

Most common pituitary adenoma of MEN1

Prolactinoma

Helps us to understand the link between genetic variation and response to medications More studies needed in the field of Type 2 DM as it may be possible to optimize and individualize treatment plans

Pharmacogenetics

Lifetime risk for a first degree relative is __-__ times higher than age and weight matched controls without a first degree relative with type 2 DM

5-10

Accounts for 90% of CAH cases Genetics: - chromosome 6p21 - allows recombination during meiosis - everyone has 2 genes, the active and non-functional pseudogene are 90% homologous - unequal crossover events where large deletions or pseudodeleterious material can cross from non-function pseudogene to active form

21 Hydroxylase Deficiency

Examination of chromosomes to identify structural abnormalities - translocations, monosomy, trisomy

Cytogenic testing

Group of AR disorders which causes a deficiency of an enzyme involved in both the synthesis of cortisol, aldosterone, or both 67% are "salt losing" - salt wasting 33% are "simple virilizing" Higher mutation rates in Ashkenazi Jews and Yupik in Alaska

CAH

Clinical features: - Cafe au lait spots - neurofibromas - axillary and inguinal freckling - optic pathway gliomas (may lead to gigantism d/t GH secretion) - lisch nodules of the iris Endocrine tumors: - pheo - paragangliomas - GI tract/pancreatic tumors

NF1

Postzygotic (mosaic) activating mutation of the alpha subunit of the stimulatory Gs protein Triad: - cafe au lait spots - fibrous dysplasia of the bone - precocious puberty

McCune-Albright Syndrome

Germline mutation in the extracellular domain of RET proto-oncogene leads to (2 conditions)

MEN2A | Familial MTC

Neurofibromatosis 1 is an AD mutation in tumor suppressor gene NF1 It expresses __ penetrance and __ expressivity - patients with same genotype, may have different clinical symptoms

Complete | Variable