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Endo > SM_193b: Endocrine Genetic Syndromes > Flashcards

SM_193b: Endocrine Genetic Syndromes Flashcards

1
Q

Describe the timing of manifestation of genetic disorders

A

Timing of manifestation of genetic disorders

  1. Chromosomal
  2. Monogenic
  3. Polygenic / multifactorial
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2
Q

Complex disorders are influenced by ___, ___, and ___

A

Complex disorders are influenced by susceptibility genes, environment / lifestyle, and mutliple genes / factors

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3
Q

Monogenic diabetes is a ___

A

Monogenic diabetes is a single gene defect (autosomal dominant) leading to development of diabetes mellitus

  • Often misdiagnosed as T2DM
  • Lack of diabetes autoantibodies
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4
Q

T2DM is caused by ___

A

T2DM is caused by a complex interaction of multiple genes and environmental factors

  • Large genetic basis: some SNPs
  • Diet and obesity: lead to peripheral resistance to insulin-mediated glucose uptake and decreased sensitivity of beta cells to glucose, lifestyle modifications in diet and exercise improve insulin sensitivity
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5
Q

____ is the most common cause of male hypogonadism

A

Klinefelter’s Syndrome is the most common cause of male hypogonadism

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6
Q

Klinefelter’s Syndrome most often has the genotype ____

A

Klinefelter’s Syndrome most often has the genotype 47 XXY

  • Due to nondisjunction of sex chromosomes
  • Can be mosaic
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7
Q

Klinefelter’s Syndrome presents with ____, ____, ____, ____, ____, and ____

A

Klinefelter’s Syndrome presents with

  • Increased length of arms and legs
  • Gynecomastia
  • Psychosocial abnormality
  • Inattention
  • Impairment of linguistic function
  • Small firm testes with low sperm count and infertility
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8
Q

Turner syndrome most often has the genotype ___

A

Turner syndrome most often has the genotype 45 XO

  • May have partial monosomy
  • May be mosaic genotype
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9
Q

Describe presentation of Turner Syndrome

A

Turner Syndrome

  • Lack of second X chromosome
  • Small ovaries with few or no follicles, streak gonads leading to infertility
  • Short stature
  • Swelling of hands and feet
  • Shield chest
  • Low set hairline
  • Heart disease
  • Horseshoe kidney
  • Ear infections and hearing loss
  • ADHD
  • Non-verbal learning disability
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10
Q

Congenital adrenal hyperplasia is ___

A

Congenital adrenal hyperplasia is a group of recessive disorders which causes a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both

  • Classical CAH: 67% are salt losing, 33% are simple virilizing
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11
Q

Congenital adrenal hyperplasia results from mutations in ___

A

Congenital adrenal hyperplasia results from mutations in steroid synthesis pathway

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12
Q

___ is the most common form of congenital adrenal hyperplasia

A

21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia

  • Prevents downstream formation of Androstenedione
  • Chromosome 6p21, allows recombination during meiosis, unequal crossover events
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13
Q

Describe mutations causing congenital adrenal hyperplasia

A

Mutations causing congenital adrenal hyperplasia

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14
Q

Males with classic virilizing CAH present at ____ with ____, ____, ____, ____, ____, and ____

A

Males with classic virilizing CAH present at age 1-4 with failure to thrive, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock

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15
Q

Females with classic virilizing congenital adrenal hyperplasia present with ____

A

Females with classic virilizing congenital adrenal hyperplasia present with ambiguous genitalia at birth due to excess androgens in utero

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16
Q

Describe tumor syndromes

A

Tumor syndromes

  • Multiple Endocrine Neoplasia
  • Pheochromocytoma / paraganglioma syndromes
  • Von Hippel Lindau
  • NF-1
  • Li Fraumeni
  • Carney Complex
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17
Q

Multiple Endocrine Neoplasia 1 affects the ____, ____, and ____

A

Multiple Endocrine Neoplasia 1 affects the parathyroid, pancreas, and pituitary

(3 P’s)

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18
Q

MEN1 presents with ____, ____, and ____

A

MEN1 presents with primary hyperparathyroidism, pituitary adenoma, and pancreatic / duodenal tumors

  • Primary hyperparathyroidism: most common manifestation, presents in 2nd-4th decade of life, generally needs treatment with 3.5 gland resection
  • Pituitary adenoma: prolactinoma is most common
  • Pancreatic / duodenal tumors: gastrinoma is most common
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19
Q

MEN1 occurs due to ___

A

MEN1 occurs due to mutation in MEN1 gene that codes for the protein menin

  • Knudsen’s two hit hypothesis: affected individuals inherit 1 mutation from a parent in autosomal dominant transmission, receive second hit leading to tumor formation
20
Q

MEN 2A presents with ___, ___, and ___

A

MEN 2A presents with medullary thyroid cancer, primary hyperparathyroidism, and pheochromocytoma

  • Hirschprung’s disease
  • Cutaneous lichen amyloidosis
21
Q

MEN 2B presents with ____, ____, and ____

A

MEN 2B presents with medullary thyroid carcinoma, pheochromocytoma, and intestinal ganglioneuromatosis

22
Q

Medullary thyroid carcinoma is ____ that occurs commonly in patients with ____

A

Medullary thyroid carcinoma is a neuroendocrine tumor of the parafollicular or C-cells of the thyroid gland that occurs commonly in patients with MEN 2

  • MEN 2A: incidence peaks in 3rd decade of life
  • MEN 2B: occurs earlier and is more aggressive
  • Early thyroidectomy is important
23
Q

____ mutation can cause medullary thyroid carcinoma

A

Somatic RET mutation can cause medullary thyroid carcinoma

  • Most is sporadic
24
Q

Describe genetics of MEN 2

A

MEN 2 genetics

  • Autosomal dominant gain of function mutation of RET proto-oncogene
  • Germline mutation in the extracellular domain: MEN2A/FMTC
  • Germline mutation: FMTC
  • Germline mutation: TK2 domain (MEN 2B)
  • Strong phenotype-genotype correlation
25
Q

Pheochromocytoma is ____

A

Pheochromocytoma is catecholamine-producing tumor in the adrenal gland

26
Q

Paraganglioma is ____

A

Paraganglioma is extra-adrenal tumor on sympathetic or parasympathetic ganglia

  • Can be secretory (abdominal) or non-functional (head and neck)
27
Q

Pheochromocytoma / paraganglioma presents with a classic triad of ____, ____, and ____

A

Pheochromocytoma / paraganglioma presents with a classic triad of episodic headache, sweating, and tachycardia

  • Half of patients will have paroxysmal hypertension as well
28
Q

Von Hippel-Lindau is an ____ syndrome due to ____

A

Von Hippel-Lindau is an autosomal dominant syndrome due to a two-hit model with germline mutation in the VHL tumor suppressor gene

29
Q

Describe the presentation of Von Hippel-Lindau

A

Von Hippel-Lindau

  • Hemangioblastomas of the brain
  • Retinal capillary hemangioblastomas
  • Clear cell renal cell carcinomas
  • Pheochromocytomas
  • Endolymphatic tumors of the middle ear
  • Neuroendocrine tumors of the pancreas
  • Papillary cystadenomas of the epididymis and broad ligament
30
Q

NF-1 results from ____ and has ____ but ____

A

NF-1 results from an autosomal dominant mutation in the tumor suppressor gene NF1 and has complete penetrance but varying expressivity

  • Penetrance: amount of people who carry a disease causing mutation that exhibit clinical symptoms
  • Expressivity: different phenotype with same genotype
31
Q

Describe presentation of NF-1

A

NF-1 presentation

  • Cafe au lait macules
  • Neurofibromas
  • Axillary and inguinal freckling
  • Optic pathway gliomas: may lead to gigantism due to GH secretion
  • Lisch nodules of the iris
  • Endocrine tumors: pheochromocytomas, paragangliomas, and GI tract / pancreatic tumors
32
Q

Li-Fraumeni results from an ___

A

Li-Fraumeni results from an autosomal dominant mutation in tumor protien p53

  • Can delay cell cycle progression to allow for DNA repair or apoptosis
  • In absence of normal p53 cells with damaged DNA can survive and proliferate
33
Q

Describe presentation of Li-Fraumeni Syndrome

A

Li-Fraumeni Syndrome presentation

  • Sarcomas
  • Premenopausal breast cancer
  • Brain tumors: gliomas, medulloblastomas
  • Adrenocortical tumors
34
Q

Carney Complex results from ____

A

Carney Complex results from autosomal dominant inactivation of PRKAR1A

35
Q

Describe presentation of Carney Compledx

A

Carney Complex

  • Adrenocortical tumors: primary pigmented nodular adrenocortical disease leads to Cushing’s syndrome, adrenocortical cancer secretes androgens and cortisol
  • Thyroid nodules (10% malignant)
  • Pituitary adenomas
  • Large cell calcifying sertoli cell tumor of testicles
  • Ovarian cysts or teratomas
  • Skin: lentigines, blue nevi, myxomas, cafe au lait spots
  • Eyes: pigmented lesions of conjunctiva and palpebra
  • Cardiac myxomas
  • Nerve sheath tumors
  • Breast myxomas
  • Osteochondromyxoma
  • Rarely: uterine myxoma, hepatocellular adenoma, pancreatic neoplasm
36
Q

McCune Albright syndrome is caused by ____

A

McCune Albright syndrome is caused by a postzygotic activating mutation of the alpha subunit of the stimulatory G-protein

  • Somatic mutation with mosaic distribution in tissues
37
Q

McCune Albright Syndrome is classically described as a triad of ____, ____, and ____

A

McCune Albright Syndrome is classically described as a triad of fibrous dysplasia of the bone, cafe au lait hyperpigmentation of the skin, and precocious puberty

38
Q

Describe presentation of McCune Albright Syndrome

A

McCune Albright Syndrome

  • Fibrous dysplasias of bone, cafe au lait hyperpigmentation of the skin, precocious puberty
  • Hyperfunctioning endocrinopathies: gonadatropin-independent precocious puberty, hyperthyroidism, GH excess, hyperprolactinemia, hypercortisolism
  • Non-endocrine manifestations: heart disease, renal phosphate wasting, and hepatobiliary dysfunction
39
Q

Describe autoimmune polyglandular syndromes

A

Autoimmune polyglandular syndromes

  • APS1: chronic candidiasis, chronic hypoparathyroidism, autoimmune adrenal insufficiency
  • APS2: autoimmune adrenal insufficiency + autoimmune thyroid disease and/or T1DM
  • APS3: autoimmune thyroid disease + other autoimmune disease
  • APS4: two or more organ-specific autoimmune disease
40
Q

People with autoimmune polyglandular syndromes are ____

A

People with autoimmune polyglandular syndromes are homozygous or compound heterozygous for mutations in the autoimmune regulator AIRE gene

  • AIRE modulates the transcription of peripheral self-antigens in the thymus presented by HLA molecules to maturing T cells
41
Q

Cytogenetic testing is ____

A

Cytogenetic testing is examination of chromosomes to identify structural abnormalities

42
Q

Biochemical testing examines ___

A

Biochemical testing examines protein, not gene

  • Ex: looking for adrenal intermediates for CAH
43
Q

Direct DNA analysis is used when ____

A

Direct DNA analysis is used when gene sequence of interest is known

  • Direct sequencing
  • PCR
  • Hybridization
  • Microarray analysis: small deletions and duplications in known disease causing regions
44
Q

Allelic heterogeneity is ____

A

Allelic heterogeneity is multiple different mutations can occur in the same gene

  • Ex: mutations in the androgen receptor gene can lead to complete androgen insensitivity or partial insensitivity
  • Must sequence the whole gene to find the defect
45
Q

Locus heterogeneity is ____

A

Locus heterogeneity is when a similar disease phenotype occurs due to mutations in different genes

  • Ex: Nephrogenic diabetes insipidus can be due to mutation on X chromosome (AVPR2 gene) or chromosome 12 (AQP2)
  • Must think of different genes to test
46
Q

Next generation sequencing is ____

A

Next generation sequencing is sequencing multiple DNA fragments in parallel

  • Must meet with genetic counselor first
  • WGS: costlier but looks at role of non-coding DNA in disease
  • WES: sequences the portion of the genes that code proteins, misses introns and regulatory regions
  • Targeted gene panels

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