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Pediatric Endocrinology. Sexual Differentiation Normal v. Abnormal Sterling M. Tanner, M.D., J.D.. F.A.A.P. Symbolism. Mr Ducks Mr Knot os Mr Cm Wangs Cm Ed BD Eyes oIB Mr Ducks. Symbolism. Mr Ducks Mr Knot os Mr Cm Wangs Cm Ed BD Eyes oIB Mr Ducks. Growth Related hGH GHRH

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pediatric endocrinology

Pediatric Endocrinology

Sexual Differentiation

Normal v. Abnormal

Sterling M. Tanner, M.D., J.D.. F.A.A.P.

symbolism
Symbolism

Mr Ducks

Mr Knot

os Mr

Cm Wangs

Cm Ed BD Eyes

oIB Mr Ducks

symbolism1
Symbolism

Mr Ducks

Mr Knot

os Mr

Cm Wangs

Cm Ed BD Eyes

oIB Mr Ducks

pediatric endocrinology is all about symbolism
Growth Related

hGH

GHRH

IgF—1

IgF—BP3

BA v. CA

-2.3 SD

Acromegaly

CAH Related

P450c11

P450c21

17OH P

11 DOC

DHEA

DHEA S

Androstenedione

Pediatric Endocrinologyis all aboutSymbolism
slide6

“Andre the Giant” -- 7’4” – 500 pounds – Died at age 47

Big Foot and Six Million Dollar Man

etiology
Etiology
  • Adrenal Tumors
    • Carcinoma
    • Adenoma
    • Not Defined
  • Ectopic ACTH syndrome
  • Nodular Adrenal Hyperplasia
  • Undefined Adrenal Hyperplasia
  • ACTH Producing Tumor

PRODUCING EXCESS CORTISOL

clinical symptoms
Clinical Symptoms

Weight Gain 92%

Growth Failure 84%

Osteopenia 74%

Fatigue 67%

Hypertension 63%

Delayed Puberty 60%

Plethora 46%

Acne 46%

Hirsuitism 46%

clinical symptoms continued
Clinical Symptoms Continued

Compulsive Behavior 44%

Striae 36%

Bruising 28%

Buffalo Hump 28%

Headache 26%

Delayed Bone Age 11%

Nocturia 8%

treatment

Treatment:

1. Find the Cause2. Remove It

normal sexual differentiation
Normal Sexual Differentiation

Don’t have time to discuss in detail.

H-Y Antigen on Short Arm of the Y Chromosome is Required.

Pseduoautosomal Region of the Y Chromosome

Recombination During Meiosis.

Testes Determining Factor ZFY Gene Initially, but can have males with out it.

SRY Gene now thought to be the Testes

Determining Factor.

virilization
Virilization

Don’t forget that virilization of the developing female (and less so the male) can occur with intrauterine exposure to Androgens or Prostaglandins.

slide14
Next We Will DiscussTwo Situationsthat are Reasonably Rare.But, you should be Aware that theyExist.
complete syndrome of androgen resistance
Complete Syndrome ofAndrogen Resistance

Previously Called Testicular

Feminization Syndrome

Follows X-linked Pattern

There is a Variable Defect

Beyond Our Scope

Phenotypic FemalesMales

1:20,000 to 1:64,000 “men”

diagnosis
Diagnosis

Not usually suspected until puberty

Normal external female phenotype

No breast development

No axillary or pubic hair

Amenorrhea

Physical Exam Reveals Either:

Inguinal Hernia v. Labial Masses

findings
Findings

Structural Issues –

No oviducts, no uterus

Only lower 1/3 of vagina

(vaginal pouch)

Prepubertal testes normal 

Lesions of Sertoli Cells

Post-pubertal  Precancerous

treatment1

Treatment

Structural Issues --

Ethical Issues --

(Jewish, Catholic, Mormons)

First Do No Harm

Do you tell? At what age?

Pure E2 replacement

↓LH Levels (LHRH)

girls are girls and boys are girls1

Girls are GirlsandBoys are Girls

Until Puberty

then

Boys are Boys

5 alpha reductase deficiency

5 alpha-ReductaseDeficiency

No Androgen Resistance

Dominican Republic & São Paulo

All Newborns are Female

huevo a los doce – “eggs at twelve”

Raised Female until Puberty

Then Progressive Virilization

Can Reproduce, but ↓ Fertility

girls are girls and boys are

Girls are GirlsandBoys are ???

Beyond Our Discussion

treatment depends on syndrome
Treatment Dependson Syndrome
  • Small Penis
  • Cryptorchidism
  • Hypogonadism
kallmann syndrome
Kallmann Syndrome

Most Common Isolated gonado-

tropin deficiency

1:10,000 births 5:1 male:female

50% males born with microphallus

Anosmia v. hyposmia also with

variable expression

Hypothalamic hypogonadism

girls are and boys are boys

Girls are ???andBoys are Boys

Or

“Super Boys”

Except Lipoid Boys

classic congenital adrenal hyperplasia
ClassicCongenital Adrenal Hyperplasia

Hundreds of Mutations Identified

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.

17 beta – Hydroxysteroid Dehydrogenase Def.

Placental Aromatase Deficiency

classic congenital adrenal hyperplasia1
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

classic congenital adrenal hyperplasia2
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

classic congenital adrenal hyperplasia3
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

classic congenital adrenal hyperplasia4
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.

classic congenital adrenal hyperplasia5
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.

17 beta – Hydroxysteroid Dehydrogenase Def.

classic congenital adrenal hyperplasia6
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.

17 beta – Hydroxysteroid Dehydrogenase Def.

Placental Aromatase Deficiency

classic congenital adrenal hyperplasia7
ClassicCongenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.

17 beta – Hydroxysteroid Dehydrogenase Def.

Placental Aromatase Deficiency

5 alpha – Reductase Deficiency

making the diagnosis
Making the Diagnosis
  • Call Pediatric Endocrinologist STAT
  • Really quite Logical, But
  • Not a Situation to Follow Step by Step Evaluation – Need Answers Fast
  • Reference Laboratories with 24-72 hr. Results
  • Check all Hormone Levels in the Path
slide57
Pregnenolone
  • 17 – Hydroxypregnenolone
  • Progesterone
  • 17 – Hydroxyprogesterone
  • Dehydroepiandrosterone / DHEA Sulfate
  • Androstenedione
  • Deoxycorticosterone
  • Aldosterone
  • 11 – Deoxycortisol
  • Cortisol and ACTH Levels (am and hs)
  • Testosterone and DHT
available now 24 48 hours
Available Now – 24 – 48 Hours
  • MRI to Identify Internal Structures
    • Testes (location)
    • Ovaries, Tubes, Uterus
  • Buccal Swab for Barr Bodies
  • Karyotype
assign sex asap decision by whom
Assign Sex – ASAPDecision by Whom?

Need as much Information as

Possible as Quickly as Possible.

Identify the Physiological Defect

Get a Surgical Consult

Religious Leader Input if Desired

Sociologist/Psychologist Counseling

Conference with Family

treatment specific to lesion
Treatment: Specific to Lesion

3 Most Common: Cortisol Synthesis

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid

Dehydrogenase Deficiency

replace missing glucocorticoid
Replace Missing Glucocorticoid

PITFALLS!!

Too Much:

Cushing Syndrome

Stunted or Delayed Growth

Too Little:

↑ Production Adrenal Androgens

Virilization

Epiphyseal Maturation & Closure

cortisol secretion
Cortisol Secretion

Classic: 12.5 ± 3 mg/m2/day

Actual: 6-7 ± 2 mg/m2/day

Consider Absorption kinetics

Treatment 10-20 mg/m2/day

Follow Circadian Rhythm (bid v. tid)

Higher doses at diagnosis

Adjust by results of lab tests q3mo

Through Puberty – Consider

Longer Acting Steroid

salt losers
“Salt Losers”

Any of these Enzymatic Abnormalities May Cause Mineralocorticoid Deficiency.

Depends on Lesion and if Alternate

Pathway

In these cases, must Add Fludrocortisone (Florinef) to Prevent “Salt Wasting”

salt losers1
“Salt Losers”

Hydrocortisone has Mineralocorticoid

Effect (0.1 mg Florinef/20mg HC)

Mild Defect May Not Require

Children: 0.05-0.15 mg/day

Adults: 0.15-0.30 mg/day

How Would You Evaluate Dose?

ethical issues
Ethical Issues

Should the Parent have the Right to:

Decide Sex Assignment at Birth?

How the Child is Raised?

What Surgery Should be Done?

If and When the Child is Told?

Should the Doctor have a say?

Should it be up to the Ethics Committee?

What about Later in Life?

Case Studies Abound – e.g.

treatment rarer defects
Treatment – Rarer Defects

Form over Function

Gonadal Hormone Tx

Stop Precursor Elevations

Stop Effects of the Defect

Monitor

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