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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


Pediatric endocrinology

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

Big Foot and Six Million Dollar Man


Etiology
Etiology at age 47

  • 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 at age 47

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 at age 47

Compulsive Behavior 44%

Striae 36%

Bruising 28%

Buffalo Hump 28%

Headache 26%

Delayed Bone Age 11%

Nocturia 8%


Treatment

Treatment: at age 47

1. Find the Cause2. Remove It


Normal sexual differentiation
Normal Sexual Differentiation at age 47

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 at age 47

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


Girls are girls and boys are boys

Girls are Girls at age 47andBoys are Boys

(Usually)


Pediatric endocrinology
Next We Will Discuss at age 47Two Situationsthat are Reasonably Rare.But, you should be Aware that theyExist.


Girls are girls and boys are girls

Girls are Girls at age 47andBoys are Girls

(Sometimes)


Complete syndrome of androgen resistance
Complete Syndrome of at age 47Androgen 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 at age 47

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 at age 47

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 at age 47

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 Girls at age 47andBoys are Girls

Until Puberty

then

Boys are Boys


5 alpha reductase deficiency

5 alpha-Reductase at age 47Deficiency

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 Girls at age 47andBoys are ???

Beyond Our Discussion


Treatment depends on syndrome
Treatment Depends at age 47on Syndrome

  • Small Penis

  • Cryptorchidism

  • Hypogonadism


Kallmann syndrome
Kallmann Syndrome at age 47

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 ??? at age 47andBoys are Boys

Or

“Super Boys”

Except Lipoid Boys


Classic congenital adrenal hyperplasia
Classic at age 47Congenital 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
Classic at age 47Congenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia


Classic congenital adrenal hyperplasia2
Classic at age 47Congenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency


Classic congenital adrenal hyperplasia3
Classic at age 47Congenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency


Classic congenital adrenal hyperplasia4
Classic at age 47Congenital Adrenal Hyperplasia

Congenital Lipoid Adrenal Hyperplasia

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid Dehydrogenase Def.


Classic congenital adrenal hyperplasia5
Classic at age 47Congenital 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
Classic at age 47Congenital 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
Classic at age 47Congenital 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 at age 47

  • 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


Pediatric endocrinology

  • Pregnenolone at age 47

  • 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 at age 47

  • MRI to Identify Internal Structures

    • Testes (location)

    • Ovaries, Tubes, Uterus

  • Buccal Swab for Barr Bodies

  • Karyotype


Assign sex asap decision by whom
Assign Sex – ASAP at age 47Decision 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 at age 47

3 Most Common: Cortisol Synthesis

21 - Hydroxylase Deficiency

11 beta – Hydroxylase Deficiency

3 beta – Hydroxysteroid

Dehydrogenase Deficiency


Replace missing glucocorticoid
Replace Missing Glucocorticoid at age 47

PITFALLS!!

Too Much:

Cushing Syndrome

Stunted or Delayed Growth

Too Little:

↑ Production Adrenal Androgens

Virilization

Epiphyseal Maturation & Closure


Cortisol secretion
Cortisol Secretion at age 47

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” at age 47

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” at age 47

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 at age 47

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 at age 47

Form over Function

Gonadal Hormone Tx

Stop Precursor Elevations

Stop Effects of the Defect

Monitor