SM_193b: Endocrine Genetic Syndromes Flashcards
Describe the timing of manifestation of genetic disorders
Timing of manifestation of genetic disorders
- Chromosomal
- Monogenic
- Polygenic / multifactorial
Complex disorders are influenced by ___, ___, and ___
Complex disorders are influenced by susceptibility genes, environment / lifestyle, and mutliple genes / factors
Monogenic diabetes is a ___
Monogenic diabetes is a single gene defect (autosomal dominant) leading to development of diabetes mellitus
- Often misdiagnosed as T2DM
- Lack of diabetes autoantibodies
T2DM is caused by ___
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
____ is the most common cause of male hypogonadism
Klinefelter’s Syndrome is the most common cause of male hypogonadism
Klinefelter’s Syndrome most often has the genotype ____
Klinefelter’s Syndrome most often has the genotype 47 XXY
- Due to nondisjunction of sex chromosomes
- Can be mosaic
Klinefelter’s Syndrome presents with ____, ____, ____, ____, ____, and ____
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
Turner syndrome most often has the genotype ___
Turner syndrome most often has the genotype 45 XO
- May have partial monosomy
- May be mosaic genotype
Describe presentation of Turner Syndrome
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
Congenital adrenal hyperplasia is ___
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
Congenital adrenal hyperplasia results from mutations in ___
Congenital adrenal hyperplasia results from mutations in steroid synthesis pathway
___ is the most common form of congenital adrenal hyperplasia
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
Describe mutations causing congenital adrenal hyperplasia
Mutations causing congenital adrenal hyperplasia
Males with classic virilizing CAH present at ____ with ____, ____, ____, ____, ____, and ____
Males with classic virilizing CAH present at age 1-4 with failure to thrive, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock
Females with classic virilizing congenital adrenal hyperplasia present with ____
Females with classic virilizing congenital adrenal hyperplasia present with ambiguous genitalia at birth due to excess androgens in utero
Describe tumor syndromes
Tumor syndromes
- Multiple Endocrine Neoplasia
- Pheochromocytoma / paraganglioma syndromes
- Von Hippel Lindau
- NF-1
- Li Fraumeni
- Carney Complex
Multiple Endocrine Neoplasia 1 affects the ____, ____, and ____
Multiple Endocrine Neoplasia 1 affects the parathyroid, pancreas, and pituitary
(3 P’s)
MEN1 presents with ____, ____, and ____
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
MEN1 occurs due to ___
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
MEN 2A presents with ___, ___, and ___
MEN 2A presents with medullary thyroid cancer, primary hyperparathyroidism, and pheochromocytoma
- Hirschprung’s disease
- Cutaneous lichen amyloidosis
MEN 2B presents with ____, ____, and ____
MEN 2B presents with medullary thyroid carcinoma, pheochromocytoma, and intestinal ganglioneuromatosis
Medullary thyroid carcinoma is ____ that occurs commonly in patients with ____
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
____ mutation can cause medullary thyroid carcinoma
Somatic RET mutation can cause medullary thyroid carcinoma
- Most is sporadic
Describe genetics of MEN 2
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
Pheochromocytoma is ____
Pheochromocytoma is catecholamine-producing tumor in the adrenal gland
Paraganglioma is ____
Paraganglioma is extra-adrenal tumor on sympathetic or parasympathetic ganglia
- Can be secretory (abdominal) or non-functional (head and neck)
Pheochromocytoma / paraganglioma presents with a classic triad of ____, ____, and ____
Pheochromocytoma / paraganglioma presents with a classic triad of episodic headache, sweating, and tachycardia
- Half of patients will have paroxysmal hypertension as well
Von Hippel-Lindau is an ____ syndrome due to ____
Von Hippel-Lindau is an autosomal dominant syndrome due to a two-hit model with germline mutation in the VHL tumor suppressor gene
Describe the presentation of Von Hippel-Lindau
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
NF-1 results from ____ and has ____ but ____
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
Describe presentation of NF-1
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
Li-Fraumeni results from an ___
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
Describe presentation of Li-Fraumeni Syndrome
Li-Fraumeni Syndrome presentation
- Sarcomas
- Premenopausal breast cancer
- Brain tumors: gliomas, medulloblastomas
- Adrenocortical tumors
Carney Complex results from ____
Carney Complex results from autosomal dominant inactivation of PRKAR1A
Describe presentation of Carney Compledx
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
McCune Albright syndrome is caused by ____
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
McCune Albright Syndrome is classically described as a triad of ____, ____, and ____
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
Describe presentation of McCune Albright Syndrome
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
Describe autoimmune polyglandular syndromes
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
People with autoimmune polyglandular syndromes are ____
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
Cytogenetic testing is ____
Cytogenetic testing is examination of chromosomes to identify structural abnormalities
Biochemical testing examines ___
Biochemical testing examines protein, not gene
- Ex: looking for adrenal intermediates for CAH
Direct DNA analysis is used when ____
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
Allelic heterogeneity is ____
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
Locus heterogeneity is ____
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
Next generation sequencing is ____
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
