191. Genetic Syndromes Flashcards
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
Classic triad of symptoms with paragangliomas/pheochromocytomas
Half of patients will have paroxysmal hypertension as well
- Episodic headache
- Sweating
- Tachycardia
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
Most common genotype is 45 XO, but may have a partial monosomy
- may be mosaic genotype
Turner Syndrome
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
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
Designates the fact that an identical or highly similar phenotype may result from mutations in different genes
Locus heterogeneity
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
Classic virilizing CAH in __:
- ambiguous genitalia at birth due to excess androgens in utero
Females
Catecholamine-producing tumor in the adrenal medulla
Pheochromocytoma
Germline mutation in TK2 (intracellular domain) of RET proto-oncogene leads to
MEN2B
In monozygotic twins where on twin has type 2 DM, there is __% chance the other twin develops type 2 DM
90
Most common types of MODY? (2 of them)
Type 2 and Type 3
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
MEN
Von Hippel Lindau
Li Fraumeni
Pheochromocytoma/Paraganglioma Syndromes
Endocrine Tumor Syndromes
Indicates that different mutations in the same gene can cause an identical or similar phenotype
Allelic heterogeneity
Most __ are lethal during early fetal development
Monosomies
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
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
AD
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
