Pediatric Endocrinology

1. Pediatric Endocrinology Sexual Differentiation Normal v. Abnormal Sterling M. Tanner, M.D., J.D.. F.A.A.P.

2. Symbolism is powerful. But, it needs to be interpreted correctly. The first line of the conversation above is ��Dem Are Ducks!� The rest of the conversation then opens up�Symbolism is powerful. But, it needs to be interpreted correctly. The first line of the conversation above is ��Dem Are Ducks!� The rest of the conversation then opens up�

3. Symbolism Mr Ducks Mr Knot os Mr Cm Wangs Cm Ed BD Eyes oIB Mr Ducks Symbolism is powerful. But, it needs to be interpreted correctly. The first line of the conversation above is ��Dem Are Ducks!� The rest of the conversation then opens up�Symbolism is powerful. But, it needs to be interpreted correctly. The first line of the conversation above is ��Dem Are Ducks!� The rest of the conversation then opens up�

4. Pediatric Endocrinologyis all aboutSymbolism 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

7. Etiology Adrenal Tumors Carcinoma Adenoma Not Defined Ectopic ACTH syndrome Nodular Adrenal Hyperplasia Undefined Adrenal Hyperplasia ACTH Producing Tumor PRODUCING EXCESS CORTISOL

8. Clinical Symptoms Weight Gain 92% Growth Failure 84% Osteopenia 74% Fatigue 67% Hypertension 63% Delayed Puberty 60% Plethora 46% Acne 46% Hirsuitism 46%

9. Clinical Symptoms Continued Compulsive Behavior 44% Striae 36% Bruising 28% Buffalo Hump 28% Headache 26% Delayed Bone Age 11% Nocturia 8%

10. Treatment: 1. Find the Cause2. Remove It

11. 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.

12. Virilization Don�t forget that virilization of the developing female (and less so the male) can occur with intrauterine exposure to Androgens or Prostaglandins.

13. Girls are GirlsandBoys are Boys (Usually)

14. Next We Will DiscussTwo Situationsthat are Reasonably Rare.But, you should be Aware that theyExist.

15. Girls are GirlsandBoys are Girls (Sometimes)

16. 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�

17. 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

18. 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

19. Treatment Structural Issues -- Ethical Issues -- (Jewish, Catholic, Mormons) First Do No Harm Do you tell? At what age? Pure E2 replacement ? LH Levels (LHRH)

20. Girls are GirlsandBoys are Girls Until Puberty then Boys are Boys

21. 5 alpha-ReductaseDeficiency No Androgen Resistance Dominican Republic & S�o Paulo All Newborns are Female huevo a los doce � �eggs at twelve� Raised Female until Puberty Then Progressive Virilization Can Reproduce, but ? Fertility

22. Girls are GirlsandBoys are ??? Beyond Our Discussion

25. Treatment Dependson Syndrome Small Penis Cryptorchidism Hypogonadism

26. 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

27. Girls are ???andBoys are Boys

28. 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

30. ClassicCongenital Adrenal Hyperplasia Congenital Lipoid Adrenal Hyperplasia

32. ClassicCongenital Adrenal Hyperplasia Congenital Lipoid Adrenal Hyperplasia 21 - Hydroxylase Deficiency

34. ClassicCongenital Adrenal Hyperplasia Congenital Lipoid Adrenal Hyperplasia 21 - Hydroxylase Deficiency 11 beta � Hydroxylase Deficiency

36. ClassicCongenital Adrenal Hyperplasia Congenital Lipoid Adrenal Hyperplasia 21 - Hydroxylase Deficiency 11 beta � Hydroxylase Deficiency 3 beta � Hydroxysteroid Dehydrogenase Def.

38. ClassicCongenital Adrenal Hyperplasia Congenital Lipoid Adrenal Hyperplasia 21 - Hydroxylase Deficiency 11 beta � Hydroxylase Deficiency 3 beta � Hydroxysteroid Dehydrogenase Def. 17 beta � Hydroxysteroid Dehydrogenase Def.

40. 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

42. 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

46. What Do You See??

55. 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

57. Pregnenolone 17 � Hydroxypregnenolone Progesterone 17 � Hydroxyprogesterone Dehydroepiandrosterone / DHEA Sulfate Androstenedione Deoxycorticosterone Aldosterone 11 � Deoxycortisol Cortisol and ACTH Levels (am and hs) Testosterone and DHT

58. Available Now � 24 � 48 Hours MRI to Identify Internal Structures Testes (location) Ovaries, Tubes, Uterus Buccal Swab for Barr Bodies Karyotype

59. 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

60. Treatment: Specific to Lesion 3 Most Common: Cortisol Synthesis 21 - Hydroxylase Deficiency 11 beta � Hydroxylase Deficiency 3 beta � Hydroxysteroid Dehydrogenase Deficiency

64. Replace Missing Glucocorticoid PITFALLS!! Too Much: Cushing Syndrome Stunted or Delayed Growth Too Little: ? Production Adrenal Androgens Virilization Epiphyseal Maturation & Closure

65. 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

66. What Else is Missing?

70. �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�

71. �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?

72. 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.

73. Least Common Defects

76. Treatment � Rarer Defects Form over Function Gonadal Hormone Tx Stop Precursor Elevations Stop Effects of the Defect Monitor