Endocrinology

Calcium

An otherwise healthy 6-week infant presents with a generalized seizure. She is exclusively breast fed. The child is somewhat sleepy with a non focal examination.

Lab data: Glucose Sodium Calcium Phosphorus Magnesium 88 mg/dL 141 mEq/L 5.1 mg/dL 9.1 mg/dL 2.1 mg/dL The most likely diagnosis is: a) Pseudohypoparathyroidism b) c) d) Hypoparathyroidism Vitamin D deficiency Albright’s hereditary osteodystrophy

Actions of PTH

1.

3.

1  hydroxylase

2.

25 OH Vit D 1,25 (OH) 2 Vit D Gut NET EFFECT

Ca PO

4

An otherwise healthy 6-week infant presents with a generalized seizure. She is exclusively breast fed. The child is somewhat sleepy with a non focal examination.

Lab data: Glucose Sodium Calcium Phosphorus Magnesium 88 mg/dL 141 mEq/L 5.1 mg/dL 9.1 mg/dL 2.1 mg/dL The most likely diagnosis is: a) Pseudohypoparathyroidism b) c) d) Hypoparathyroidism Vitamin D deficiency Albright’s hereditary osteodystrophy

An otherwise healthy 6-week infant presents with a generalized seizure. She is exclusively breast fed. The child is somewhat sleepy with a non focal examination.

Lab data: Glucose Sodium Calcium Phosphorus Magnesium 88 mg/dL 141 mEq/L 5.1 mg/dL 9.1 mg/dL 2.1 mg/dL What is an important diagnostic consideration (i.e. what else is the child at risk for) DiGeorge syndrome – thymic aplasia, congenital heart disease, immune deficiency

Biochemical changes in rickets

Ca

Stage 1 Stage 2 N

PO

4 N

Bone

Minimal changes

Urine

Rickets Aminoaciduria Phosphaturia

Initial 2 ½ weeks 4 months Ca: PO 4 : Alk Phos: 9.7

3.1

2514 9.8

3.5

2185 10.5

6.5

518

Which is consistent with vitamin D deficiency rickets?

CALCIUM PHOS ALK PHOS A. Normal B. Low C. Low D. Low E.

Normal Normal Low Increased Normal Low Low Low Increased Normal Increased

Choose correct answer

A.

B.

C.

D.

Vitamin D deficiency rickets Renal osteodystrophy (renal rickets) Both Neither

1. Increased phosphate level B 2. Increased PTH level C 3. Increased creatinine level B

THYROID

TSH T4 A 15 day infant has an abnormal newborn thyroid screen result: The baby was born on 5/27/07. His newborn screening tests, performed on 5/29/07 revealed: 37  10.1 IU/ml  g/dl Normal range < 20 9-19 This child: a) Has congenital hypothyroidism and should be referred to a congenital hypothyroidism treatment center b) Will likely develop mental retardation if untreated c) Likely does not have any thyroid abnormality d) Has an altered hypothalamic set-point for T4 e) Should be started on thyroxine replacement immediately

You are contacted by your state Neonatal Thyroid Screening Program. Baby X was born on 1/4/01. His newborn screening tests, performed on 1/6/01 revealed:

Initial filter paper

TSH T4 >200  IU/ml 2.1  g/dl Normal range < 20 9-19

Venipuncture:

(1/25/01) TSH T4 488  IU/ml 1.2  g/dl Normal range (0.3-5.5) (4.5-12.5)

Congenital hypothyroidism

      Thyroid dysgenesis/agenesis Prevalence 1 in 4,000 [Whites 1 in 2,000; Blacks 1 in 32,000] 2:1 female to male ratio Clinical features include: hypotonia, enlarged posterior fontanelle, umbilical hernia, indirect hyperbilirubinemia Laboratory findings: Therapy: Thyroxine Very high TSH and low T4 – keep TSH in normal range

6 month female with congenital hypothyroidism ..following 4 months therapy

A baby who was born with gastroschisis has an abnormal newborn thyroid screen at 3 days which revealed a low T4 and normal TSH. Repeat venipuncture showed: T4 2.1 μg/dL (4.5-12.5) TSH 2.3 μIU/mL (0.3-5.0) a) b) c) d) e) The most likely diagnosis is: Hypothyroidism due to dysgenesis of the thyroid gland Central hypothyroidism TBG deficiency Hypothyroidism from excess iodine exposure Normal thyroid function (as the TSH is normal)

Central hypothyroidism - rare vs.

TBG deficiency 1:2800

Thyroxine (T4)

  Major product secreted by the thyroid  Circulates bound to thyroid binding proteins - thyroid binding globulin (TBG)  Only a tiny fraction (< 0.1%) is free and diffuses into tissues When we measure T4, we measure the T4 that is bound to protein  The level of T4 is therefore largely dependent on the amount of TBG  Changes in T4 may reflect TBG variation rather than underlying pathology

Free T4 TBG level T3RU

Central hypothyroidism TBG deficiency

Low Normal Low Normal Low High

17 year old female who complains of easy fatigability. Her mother developed Graves’ disease at the same age.

Thyroid function:

TSH: 3.7  IU/ml T4: 13.4  g/dl

Normal range

0.3-5.5

4.5-12

17 year old female who complains of easy fatigability. Her mother developed Graves’ disease at the same age.

Thyroid function:

TSH: 3.7  IU/ml T4: 13.4  g/dl

Normal range

0.3-5.5

4.5-12 Which of the following medication could explain the thyroid function abnormality a) INH b) Ortho Tri-Cylen c) Retinoid acid d) Ciprofloxacin e) Doxycycline

Conditions that cause alterations in TBG

Increased TBG

Infancy Estrogen - OC Pill - pregnancy Familial excess Hepatitis Tamoxifen treatment

Decreased TBG

Familial deficiency Androgenic steroid treatment Glucocorticoids (large dose) Nephrotic syndrome Acromegaly

A 12-yr female has diffuse enlargement of the thyroid. She is asymptomatic. Her disorder is most likely associated with which of the following pathological processes a) Infectious b) Inflammatory c) Autoimmune d) Toxic (drug) e) Neoplastic

Normal thyroid Hashimoto thyroiditis

DC

 16 year 7 month  Growth failure x 1 1/2 years 

Labs

: TSH: T4:

1008

µIU/ ml

<1.0

µg/dl (0.3-5.0) (4-12) Antithyro Ab. A-perox Ab.

232 592

U/ml IU/ml Prolactin: Cholesterol:

29 406

ng/ml mg/dl (0-1) (<0.3) (2-18) (100-170)

DC

Start of thyroxine

Hashimoto thyroiditis

Background

: Autoimmune destruction of the thyroid Family history in 30-40% Lymphocytic infiltration

Clinical

: Growth failure, constipation, goiter, dry skin, weight gain, slow recoil of DTR

Laboratory

: High TSH Anti-thyroglobulin and anti-peroxidase antibodies

Therapy

: Thyroxine

15 year old female with a history of easy fatigability. Found to have an elevated pulse rate at recent MD visit

Thyroid function:

TSH < 0.1  IU/ml T4 14.8  g/dl T3 580 ng/dl

Normal range

0.3-5.5

4.5-12 90-190

Eye changes Increased GFR - polyuria Menstrual abnormalities Myopathy Restlessness, poor attention span Goiter Tachycardia, wide pulse pressure Diarrhea

Therapy for Graves disease:

Antithyroid medication (Methimazole or Propylthiouracil [PTU]) Pros : 25% remission rate every 2 years Cons: Drug induced side effects - skin rashes, agranulocytosis, lupus-like reaction Radioactive iodine ( 131 I) Pros : Easy. Essentially free of side effects Cons: Long term hypothyroidism Surgery  Blockers if markedly hyperthyroid

Sexual differentiation

Ambiguous genitalia is found in a newborn.

The baby is noted to be hyperpigmented. Ultrasound demonstrates the presence of a uterus. The most useful test to aid in the diagnosis of this medical condition is

:

a) b) c) d) e) Testosterone 17-hydroxyprogesterone Serum sodium and potassium DHEAS DHEAS/androstenedione ratio

Cholesterol Desmolase Pregnenolone 17-OH 3  -HSD 17 (OH) pregnenolone 3  -HSD Progesterone 17-OH 21-OH 17 (OH) progesterone 21-OH DOCA 11-OH Corticosterone Compound S 11-OH CORTISOL ALDOSTERONE DHEA 3  -HSD Androstenedione TESTOSTERONE

a) b) c) d) e) If she has salt wasting congenital adrenal hyperplasia, which abnormalities are likely to develop. True or False for each Increased serum potassium Decreased serum sodium Decreased bicarbonate Decreased plasma cortisol Increased plasma renin activity T T T T T

A 1-year male infant has non palpable testes. Of the following, the most appropriate next step would be a) Schedule a re-examination in 18 months b) Refer the patient for an exploratory laparotomy c) Begin therapy with LHRH d) Measure the plasma testosterone after stimulation with HCG e) Begin therapy with testosterone enanthate, 50 mg IM monthly for 3 months.

History

9 day old male infant 1 day history of decrease feeding, vomiting and lethargy.

Examination

Ill appearing infant with poor respiratory effort Vital signs: T 99  F HR 100/min BP 61/40 RR 24/min Resp: Subcostal retractions but clear to auscultation Cardiac: Abdomen: Regular rate and rhythm. Normal S1 and S2 Soft, non distended. Non tender. No HSM Neuro: Genitalia: Lethargic. No focal deficit Normal male. Bilateral descended testes

Laboratory data:

WBC 16.7

Hb 16.4

Hct 49 Plt 537 K Na K 121 9.3

Cl CO 2 Glucose 83 6.7

163 BUN/Creat 33/0.2

CSF:

Chemistry: Protein 74 Glucose Microscopy: WBC 6 RBC 82 100

Emergency therapy

Fluid resuscitation: 20 ml/kg Normal saline Glucocorticoid 2 mg/kg Solucortef IV Monitor EKG

Modes of presentation

Classical



Simple virilizing



Virilizing with salt loss “Non classical” / Late onset

Therapy and evaluation of therapy

Glucocorticoid (Hydrocortisone)  Monitor growth, 17-OHP, urinary pregnanetriol Fluorocortisol (Florinef 0.1 – 0.45 mg/day)  Blood pressure, plasma renin activity (PRA) Supplemental salt  Until introduction of infant food

History

15 year female presents with primary amenorrhea Breast development began at 10 years

Examination

Height: 5 ft 7 in Weight 130 lb Tanner 5 breast development Scant pubic hair What is your diagnosis?

Complete androgen insensitivity

XY Genotype Testosterone

Androgen Receptor

Estradiol

Estrogen Receptor

History

15 year female presents with primary amenorrhea Breast development began at 10 years

Examination

Height: 5 ft 7 in Weight 130 lb Tanner 5 breast development Scant pubic hair a) b) c) d) e) Which of the following clinical features is the most likely to give you the correct diagnosis Blood pressure in all 4 extremities Careful fundoscopic examination Rectal examination Measurement of blood pressure with postural change Cubitus valgus and shield shaped chest

Complete androgen insensitivity

     XY genotype Non functioning androgen receptor Sertoli cells – AMH  Regression of Mullerian structures Leydig cells – testosterone   No functioning receptor Therefore Wolffian regression Testosterone converted to DHT – No functioning receptor – Therefore normal female external genitalia

Early Puberty

The earliest sign of puberty in a male is: a) Enlargement of the penis b) Enlargement of the testes c) Growth acceleration d) Pubic hair growth e) Axillary hair growth

2 year old girl with breast development

– No growth acceleration – No bone age advancement – No detectable estradiol, LH or FSH The most likely diagnosis is: a) Ingestion of her mother’s OCPs b) Precocious puberty c) Premature adrenarche d) Premature thelarche e) McCune Albright Syndrome

Benign Premature Thelarche

Isolated breast development – 80% before age 2 – Rarely after age 4 Not associated with other signs of puberty (growth acceleration, advancement of bone age) Children go on to normal timing of puberty and normal fertility Benign process Routine follow-up

5 year female with 6 months of pubic hair growth. Very fine axillary hair as well as adult odor to sweat.

No breast development No exposure to androgens Growth chart: Normal growth without growth acceleration Most likely diagnosis: 1. Precocious puberty 2. Benign premature adrenarche 3. Non-classical congenital adrenal hyperplasia 4. Adrenal tumor 5. Pinealoma

Benign Premature Adrenarche

Production of adrenal androgens before true pubertal development begins Presents as isolated pubic hair in mid childhood – No growth acceleration – No testicular enlargement in boys If normal growth rate, routine follow-up If accelerated growth and/or bone age advancement, screen for – CAH – Virilizing tumor (adrenal/gonadal)

Choose correct answer

A.

B.

C.

D.

Premature theralche Premature adrenarche Both Neither 1. Growth acceleration 2. Normal adolescent sexual development 3. Onset of gonadal function usually in 2-3 years D C B

You suspect a 16 year female has Turner syndrome. The most definitive diagnostic test is a) Buccal smear b) Chromosome analysis c) Measuring her FSH and LH d) Determining her bone age e) Determining her testosterone level

5 year old girl with pubic hair and rapid growth. She has no breast development Possible sources of androgens: 1.Liver

F 2.Adrenal

3.Ovary

T T 4.Pituitary

5.Pineal

F F

5 year old girl with pubic hair and rapid growth. She has no breast development Which of the following should be considered Answer T or F for each: a) Central precocious puberty b) Congenital adrenal hyperplasia F T c) McCune Albright syndrome d) Benign premature adrenarche e) Adrenal tumor F F T

When does puberty occur?

Classic teaching – 8 -13 in girls (menarche ~ 2 years after onset of puberty) – 9 -14 in boys

Case:

Breast development: 6 years Mother had menarche: 9.5 years

Reactivation of hypothalamic – pituitary –gonadal axis

Why

Gonadatropin dependent (central) precocious puberty Clock turns on early Idiopathic > 95 % girls ~ 50 % boys

– Hypothalamic hamartoma (Gelastic seizures) – NF (optic glioma) – Head trauma – Neurosurgery – Anoxic injury – Hydrocephalus

Treatment

Why – Psychosocial – Height What – GnRH agonist

Precocious puberty in the male

Gonadotropins

Prepubertal

Gonadotropin independent precocious puberty

LH Pubertal

Central precocious puberty

Leydig cell

G

Precocious puberty in the male

Gonadotropins

Prepubertal  HCG

Gonadotropin independent precocious puberty

*

* G

Familial male Precocious puberty McCune Albright syndrome (testotoxicosis) LH Pubertal

Central precocious puberty G

Leydig cell 1. Gonadotropin independent PP 2. Polyostotic Fibrous Dysplasia 3. Café au lait macules

This child may well develop 1. Hypothyroidism 2. Acoustic neuroma 3. Precocious puberty 4. Hypocalcemia and hyperphosphatemia 5. Optic nerve hypoplasia

Growth disorders and delayed puberty

Delayed puberty

Hypogonadism

Hypergonadotropic Hypogonadism ( ↑FSH, LH) Primary gonadal failure - Chromosomal - iatrogenic (cancer therapy) - autoimmune oophoritis - galactosemia - test. biosynthetic defect Hypogonadotropic Hypogonadism (  FSH, LH) Constitutional delay Central Hypogonadism - Isolate gonad. def. - MPHD - Kallmann (anosmia) - Functional

A 15 yr boy has short stature and delayed puberty. He is now in early puberty (Tanner 2). His parents are of average stature. His height and weight are just below 3 rd percentile. All of the following are likely except: a) A bone age of 12 ½ years b) Growth hormone deficiency c) Adult height in the normal range d) Acceleration of growth and sexual maturation over the next 2 years.

e) History of normal length and weight at birth

A 15 yr male has delayed puberty. He also has headaches, diplopia and increased urination. His height is < 3 rd percentille Which of the following is the most likely diagnosis?

a) Diabetes mellitus b) Pinealoma c) Cerebellar tumor d) Craniopharyngioma e) Pituitary adenoma

A 14 yr male has tender gynecomastia (3 cm in diameter bilaterally). He is in early to mid puberty. In most cases the best management for this gynecomastia is: a) Treatment with an anti-estrogen (e.g. Tamoxifen) b) Treatment with an aromatase inhibitor c) Treatment with a dopamine agonist (bromocryptine) d) Surgery e) Reassurance

Miscellaneous

Hypoglycemia

Decreased substrate – Poor intake – Defective glycogenolysis or gluconeogenesis Increase utilization – Sepsis – Hyperinsulinism Absent counter regulatory hormones – GH – Cortisol

Choose correct answer

A.

B.

C.

D.

Hypoglycemia from hyperinsulinemia Hypoglycemia from metabolic fuel depletion Both Neither 1. Usually preceded by ketosis 2. Brisk respones to glucagon 3. Usually responds to oral glucose B A B

Side effects of corticosteroids include all of the following except a) hypertension b) hypoglycemia c) decrease bone mineralization d) myopathy e) cataracts

What is the most likely diagnosis in this newborn infant?

1. Mother has SLE 2. Anasarca from cardiac failure 3. Systemic allergic reaction 4. Congenital nephrotic syndrome 5. Turner syndrome

5 year old male with short stature 1. Turner syndrome 2. VATER syndrome 3.

Albright’s hereditary osteodystrophy 4. Noonan syndrome 5. Goldenhar syndrome

A moderately obese adolescent female has irregular periods, hirsutism and acne Of the following, which is the most likely diagnosis?

a) Cushing syndrome b) Polycystic ovarian syndrome c) Virilizing adrenal tumor d) Non-classical CAH e) Hyperprolactinemia

Choose correct answer

A.

B.

C.

D.

Diabetes mellitus Diabetes insipidus Both Neither

1. Osmolality of serum > 300 Osm/L 2. Osmolality of urine > 500 mOsm/L 3. Hypernatremia C A B