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Endocrine > 191. Genetic Syndromes > Flashcards

191. Genetic Syndromes Flashcards

1
Q

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

A

MTC

RET

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2
Q

Classic triad of symptoms with paragangliomas/pheochromocytomas

Half of patients will have paroxysmal hypertension as well

A
  1. Episodic headache
  2. Sweating
  3. Tachycardia
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3
Q

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
A

Von Hippel-Lindau

Mutations in the VHL gene

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4
Q

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

A

Turner Syndrome

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5
Q

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
A

MEN2A

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6
Q

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

A

Type 3 MODY

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7
Q

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

A

Locus heterogeneity

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8
Q

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

A

Klinefelter’s Syndrome

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9
Q

Classic virilizing CAH in __:

- ambiguous genitalia at birth due to excess androgens in utero

A

Females

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10
Q

Catecholamine-producing tumor in the adrenal medulla

A

Pheochromocytoma

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11
Q

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

A

MEN2B

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12
Q

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

A

90

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13
Q

Most common types of MODY? (2 of them)

A

Type 2 and Type 3

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14
Q

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
A

McCune-Albright Syndrome

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15
Q

MEN
Von Hippel Lindau
Li Fraumeni
Pheochromocytoma/Paraganglioma Syndromes

A

Endocrine Tumor Syndromes

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16
Q

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

A

Allelic heterogeneity

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17
Q

Most __ are lethal during early fetal development

A

Monosomies

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18
Q

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
A

Gastrinomas

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19
Q

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

A

Type 2 MODY

20
Q

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

A

RET

21
Q

AD

Classic manifestations = 3 Ps

  • parathyroid
  • pancreas
  • pituitary
A

MEN 1

22
Q

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

A

AIRE

23
Q

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

A

MEN2B

24
Q

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

A

Males

25
Q

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)

A

Monogenic Diabetes (MODY)

26
Q

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

A

Turner Syndrome

27
Q

What do you treat classic virilizing CAH with?

A

Hydrocortisone and salt supplementation

28
Q

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
A

Carney complex

29
Q

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

A

Paraganglioma

30
Q

Most common manifestation of MEN 1

  • presents in 2nd-4th decade of life
  • generally needs treatment with 3.5 gland resection
A

Primary hyperparathyroidism

31
Q

Mutated protein in MEN1

Undergoes “two hit” hypothesis

A

Menin

32
Q

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
A

Li Fraumeni Syndrome

33
Q

Marfinoid Habitus with scoliosis

High-arched palate

Megacolon

Neuromas on tongue, mouth, and eyelid

A

MEN2B (specific phenotype)

34
Q

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

A

Polygenic

35
Q

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

A

Familial MTC

36
Q

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
A

Klinefelter’s Syndrome

37
Q

Examines the protein instead of the gene

- ex: looking for adrenal intermediates for CAH

A

Biochemical testing

38
Q

Most common pituitary adenoma of MEN1

A

Prolactinoma

39
Q

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

A

Pharmacogenetics

40
Q

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

A

5-10

41
Q

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
A

21 Hydroxylase Deficiency

42
Q

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

A

Cytogenic testing

43
Q

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

A

CAH

44
Q

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
A

NF1

45
Q

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
A

McCune-Albright Syndrome

46
Q

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

A

MEN2A

Familial MTC

47
Q

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

A

Complete

Variable

Endocrine (26 decks)

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