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D&T 4, Exam 3 (Liver) > Leidy - Topics in Genetics in Clinical Endocrinology > Flashcards

Leidy - Topics in Genetics in Clinical Endocrinology Flashcards

1
Q

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?

A

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

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2
Q

What condition?

-impaired cortisol synthesis

-AR

-mostly 21-hydroxylase deficiency

A

Congenital Adrenal Hyperplasia (CAH)

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3
Q

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
A

Classic

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4
Q

Classic or Nonclassic Congenital Adrenal Hyperplasia?

-Mild

  • No genital ambiguity
  • Onset usually in adolescence
  • *-Androgen excess
  • Oligomenorrhea
  • Hirsutism
  • Acne**

-No adrenal insufficiency

A

Nonclassic

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5
Q

Fact: Steroid Biosynthetic Pathways

A

Simplified Version

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6
Q

What substrate are you looking for when diagnosis Congenital Adrenal Hyperplasia (CAH)?

A

17-OH-Progesterone

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7
Q

Facts: Genetics of 21-Hydroxylase Locus

  • HLA linkage
  • 6p21.3
  • 21-hydroxylase genes
A
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8
Q

What 3 Genetic Changes in Salt-Wasting CAH?

Which one is most likely?

1.

2.

3.

A

1. Point Mutations - 75%

  1. Gene Deletion - 12%
  2. Large Gene Converstion - 12%
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9
Q

Enzyme Activity in 21-Hydroxylase Deficiency.

Which type maintained the most enzyme activity = production of aldosterone?

A

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)

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10
Q

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

A
  1. Glucocorticoid Tx
  2. Mineralcorticoid Tx
  3. Genital Reconstruction
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11
Q

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

A

Dexamethasone (20 mcg/kg) crosses placenta, ideally before 6 weeks

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12
Q

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
A
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13
Q

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?

A

Multiple Endocrine Neoplasia (MEN) Syndromes

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14
Q

MEN Syndrome, Type 1

THE 3 P’s –> NAME THEM!

-Autosomal Dominant*

A

Parathyroid neoplasia

Pituitary Neoplasia

Pancreatic Islet Neoplasia

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15
Q

MEN Syndrome, Type 2

What does TPP stand for?

-Autosomal Dominant*

A

Thyrocalcitonin (Medullary Carcinoma)

Pheochromocytoma

Parathyroid Neoplasia

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16
Q

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*

A
17
Q

What MEN Syndrome?

-Medullary Thyroid Carcinoma 100% ******

  • Pheochromocytoma 50%
  • Parathyroid Neoplasia 10-20%
A

MEN 2A

18
Q

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

A
19
Q

What MEN Syndrome?

  • Medullary Thyroid Carcinoma 100% *******
  • Pheochromocytoma 50%
  • NO parathyroid disease *****
  • Marfinoid habitus nearly 100%
  • Intestinal ganglioneuormatosis and mucosal neuromas nearly 100%
A

MEN 2B

20
Q

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

A

Medullary Thyroid Carcinoma

Surgical

21
Q

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

A
22
Q

List the syndromes associated with Medullary thyroid carcinoma in order of most to least aggressive:

A

**MEN2B >> Sporadic = MEN 2A > FMTC

23
Q

What chromonsome is MEN 2A gene located on?

A

Chr 10

24
Q

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
A

RET Proto-Oncogene

25
Q

Fact: RET Structure and RET/GDNF Signaling System

A
26
Q

MEN 2A Screening - Pre-RET Analysis

Name the 3 Measurements and Frequency

A
27
Q

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.

A
  1. Thyroidectomy appropraite age (before 5 year) OR
  2. Annual calcitonin and neck US until abnormal –> thyroidectomy
  3. Continue catecholamine and Calcium Screening
28
Q

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
A
29
Q

True or False?

With Sporadic Medullary Thyroid Carcinoma, absence of family history does not exclude mutation.

A

TRUE!

  • 7% germline mutation
  • If no mutation, hereditary excluded with 99% certainty.
  • Somatic RET mutations in 65%
30
Q

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
A

D&T 4, Exam 3 (Liver) (19 decks)

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