Leidy - Topics in Genetics in Clinical Endocrinology Flashcards
Clinical Examples: different mutations of the same gene - NAME CONDITION?
(1) You are working in a NYC newborn nursery – a child is born with ambiguous genitalia. What is the likely diagnosis? What are the genetic implications?
(2) In the same nursery, a 1 week old male child is admitted with severe hypovolemia with marked hyperkalemia. What is the likely diagnosis? What are the genetic implications?
(3) In your office, a 16 y/o presents with irregular periods (oligomenorrhea) and hirsutism. What genetic diagnosis should be considered?
Congenital Adrenal Hyperplasia (CAH) aka 21-Hydroxylase Deficiency
(1) Classic, Simple Form (no salt-wasting)
(2) Classic, Salt-Wasting Form (Crisis: Hypovolemic Shock, Hyperkalemia)
(3) NonClassic
What condition?
-impaired cortisol synthesis
-AR
-mostly 21-hydroxylase deficiency
Congenital Adrenal Hyperplasia (CAH)
Classic or Nonclassic Congenital Adrenal Hyperplasia?
- large hyperplastic adrenals at birth
- ambigious genitalia (“adrenogenital syndrome”)
- Simple (virilizing) Form 25% (no salt-wasting)
- Salt-wasting 75% (Crisis: Hypovolemic Shock, Hyperkalemia)
- High risk of adrenal insufficiency
- Precocious puberty
- Short Stature
Classic
Classic or Nonclassic Congenital Adrenal Hyperplasia?
-Mild
- No genital ambiguity
- Onset usually in adolescence
- *-Androgen excess
- Oligomenorrhea
- Hirsutism
- Acne**
-No adrenal insufficiency
Nonclassic
Fact: Steroid Biosynthetic Pathways
Simplified Version
What substrate are you looking for when diagnosis Congenital Adrenal Hyperplasia (CAH)?
17-OH-Progesterone
Facts: Genetics of 21-Hydroxylase Locus
- HLA linkage
- 6p21.3
- 21-hydroxylase genes
What 3 Genetic Changes in Salt-Wasting CAH?
Which one is most likely?
1.
2.
3.
1. Point Mutations - 75%
- Gene Deletion - 12%
- Large Gene Converstion - 12%
Enzyme Activity in 21-Hydroxylase Deficiency.
Which type maintained the most enzyme activity = production of aldosterone?
Nonclassic: 20-50%
Simple Virilizing Classic: 1% (enough to make enough Aldo to retain Na+ to keep you out of salt-wasting crisis)
Salt-Wasting Classic: 0% (NO Aldo production)
What are 3 types of effective treatment for 21-Hydroxylase Deficiency (CAH)?
1.
2.
3.
Genetic Counseling: Birth of CAH child, adolescent transition to adult
- Glucocorticoid Tx
- Mineralcorticoid Tx
- Genital Reconstruction
What drug can be given to a mother who is identified with a CAH fetus?
-prevents fetus from making a lot of androgens so female child will be born with phenotypically normal genitalia; wouldn’t apply to men bc mascularized.
-no evidence of intellectual disabling effect
Dexamethasone (20 mcg/kg) crosses placenta, ideally before 6 weeks
Prenatal Management of Pregnancy at risk for 21-Hydroxylase Deficiency
- *Chorionic villus sampling at 8 - 10 weeks**
- Karyotype
- DNA analysis
- *Amniocentesis - 16 weeks**
- Karyotype
- DNA analysis
- HLA typing
- Amniotic fluid 17-OH progesterone
- *Fetal DNA - on the horizon**
- Extracted from maternal blood
- As early as 6 weeks
- Would limit treatment to affected females
What Condition?
(1) A 30 y/o women presents with a thyroid nodule. Her father had labile hypertension and died of a “thyroid cancer” at the age of 35. What diagnosis should you consider strongly?
(2) A 18 y/o male gives a extensive family history of thyroid cancer – mother, maternal uncles and aunts, and cousins. What is a likely diagnosis? What genetic tests would you consider given additional clinical information?
(3) A 45 y/o female is diagnosed with medullary thyroid carcinoma, which is surgically excised. What genetic test should be done and why?
Multiple Endocrine Neoplasia (MEN) Syndromes
MEN Syndrome, Type 1
THE 3 P’s –> NAME THEM!
-Autosomal Dominant*
Parathyroid neoplasia
Pituitary Neoplasia
Pancreatic Islet Neoplasia
MEN Syndrome, Type 2
What does TPP stand for?
-Autosomal Dominant*
Thyrocalcitonin (Medullary Carcinoma)
Pheochromocytoma
Parathyroid Neoplasia
Fact: Men Syndrome, Type IV
–Mutation: Cyclin-dependent kinase inhibitor-1B gene (660778)
–Multiple systems
•Respiratory – Bronchial carcinoid
•Renal - angiomyolipoma
•Endocrine – acromegaly, pituitary adenoma, parathyroid adenoma, carcinoid tumors
• Neoplasia – pancreatic endocrine neoplasia, papillary thyroid cancer, neuroendocrine carvical carcinoma
–Onset of tumors usually in adulthood
–Autosomal dominant*
What MEN Syndrome?
-Medullary Thyroid Carcinoma 100% ******
- Pheochromocytoma 50%
- Parathyroid Neoplasia 10-20%
MEN 2A
Fact: MEN 2A Variants
–Familial medullary thyroid carcinoma (FMTC)
•Local family with C609Y
–MEN 2A with cutaneous lichen amyloidosis (MEN-2A/CLA)
–MEN 2A with Hirschsprung disease
What MEN Syndrome?
- Medullary Thyroid Carcinoma 100% *******
- Pheochromocytoma 50%
- NO parathyroid disease *****
- Marfinoid habitus nearly 100%
- Intestinal ganglioneuormatosis and mucosal neuromas nearly 100%
MEN 2B
What Thyroid Cancer? Treatment?
-neoplasm of parafollicular (C) Cells
Secretory: calcitonin, CEA, other peptides
Sporadic: 70%
Familial: MEN2A, MEN2B, Familial MTC
Hyperplasia –> Nodular Hyperplasia –> Microcarcinoma –> Macrocarcinoma
Medullary Thyroid Carcinoma
Surgical
Fact: Medullary Thyroid Carcinoma
- 80% Indolent: easy to take care of
- Aggressive: metastasize eary to liver, bone, lung
**MEN2B >> Sporadic = MEN 2A > FMTC
-Death: airway obstruction, liver and lung metastases
List the syndromes associated with Medullary thyroid carcinoma in order of most to least aggressive:
**MEN2B >> Sporadic = MEN 2A > FMTC
What chromonsome is MEN 2A gene located on?
Chr 10
what gene?
- Rearranged during Transfection
- tyrosine kinase receptor
- interacts with Glial Cell-Derived Neurotrophic Factor (GDNF)
- GDNF Receptor Alpha - complexes with RET to form complete receptor
- point mutations: site of mutation determines extent of disease
RET Proto-Oncogene
Fact: RET Structure and RET/GDNF Signaling System
MEN 2A Screening - Pre-RET Analysis
Name the 3 Measurements and Frequency
RET Genetic Testing
- *MEN 2A or FMTC Kindred-Known Mutations: Normal RET Analysis**
- > find mutation and screen all affected members
- > excludes with nearly 100% certainty
- > no catecholamines or calcium screening
- *RET Mutation: ??
1. **
2.
3.
- Thyroidectomy appropraite age (before 5 year) OR
- Annual calcitonin and neck US until abnormal –> thyroidectomy
- Continue catecholamine and Calcium Screening
FACT: RET GENETIC TESTING
Familial Medullary Thyroid Carcinoma
- 5-8% of families have no known RET mutation occurs
- At risk, annual calcintonin and neck US
- repeat genetic analysis when more mutations known
True or False?
With Sporadic Medullary Thyroid Carcinoma, absence of family history does not exclude mutation.
TRUE!
- 7% germline mutation
- If no mutation, hereditary excluded with 99% certainty.
- Somatic RET mutations in 65%
SUMMARY:
- AR 21-hydroxylase deficiency has multiple clincal presentation related to enzyme activity
- newborn screening has been implemented in all states
- genetic testing is important clinically
- Female virilization can potentially be prevented with fetal genetic testing and appropriate treatment
- Genetics made important contributions in understanding MEN 2 Syndrome
- Genetics testing is established in diagnosis/Tx for MEN 2 - enabling prophylactic thyroidectomy and saves family members extensive prospective testing
- RET screening should be done in all patients with new medullary thyroid carcinoma
