Pediatric Endocrine Disorders - Exam Prep Notes

Growth

The epiphyseal (growth) plate is the area of elongation in a long bone.
Growth is mediated by Growth Hormone from the anterior pituitary gland:
- Released by GHRH from the hypothalamus.
- Inhibited by somatostatin.
Growth Pattern:
- Extraordinary fetal growth:
  - Approximately 50 cm in 9 months, representing the most rapid phase of human growth.
- Marked deceleration of growth immediately after birth, growing ~15-20 cm/year.
- Childhood phase: Growth velocity remains fairly constant at 4–7 cm/year.
- Adolescent Growth at puberty
Stadiometer → for height:
- Setup: Place the stadiometer on a flat, stable surface.
- Position the person: Have the person stand straight with their back against the stadiometer, feet flat on the floor, and heels together.
- Align the Head: Make sure the person’s head is level, looking straight ahead. The Frankfort plane (an imaginary line from the bottom of the eye socket to the top of the ear) should be horizontal.
- Lower the Headpiece: Gently lower the headpiece until it touches the top of the person’s head.
Infantometer → for length
Fastest Growth (PHV):
- Boy: Around 13.5 years old with a growth rate of about 9.5 cm/year, between stages 3 and 4 of puberty.
- Girl: Around 11.5 years old with a growth rate of about 8.3 cm/year, between stages 2 and 3 of puberty.
Complete:
- Boy: By stage 5 in more than 95% of boys.
- Girl: Limited growth, usually about 2.5 cm more.
Short stature

Short Stature

Short stature is defined as a height >2 SD below the mean, with severe short stature being defined as a height >3 SD below the mean.
Male MidParental Height (MPH) $= \frac{Father's \ height + Mother's \ height + 5 \ inches (13 \ cm)}{2}$
Female MidParental Height (MPH) $= \frac{Father's \ height + Mother's \ height - 5 \ inches (13 \ cm)}{2}$
Differential diagnosis of short stature:
- Endocrine disorders: Growth hormone deficiency, Cushing syndrome, Laron syndrome
- Chromosomal disorders: Turner syndrome, Silver–Russell syndrome, Noonan syndrome
- Systemic disease: Crohn’s disease, Juvenile arthritis, Coeliac disease, Chronic renal failure
- Others: Constitutional delay of growth/puberty, Familial short stature, Poor nutrition
Constitutional Delay of Growth and Puberty (CDGP):
- Short stature with a delayed bone age, late onset of puberty and a minimum growth velocity of 2 inches (or 5 cm) per year.
- Individual reaches a normal adult height.
Growth hormone deficiency:
- When to Investigate for GHD:
  1. Severe Short Stature: Height more than 3 standard deviations (SD) below the average.
  2. Height Below Expected Based on Parents: Height more than 1.5 SD below the mid-parental height.
  3. Height and Growth Rate Issues:
    - Height more than 2 SD below the average.
    - Growth rate over 1 year more than 1 SD below the average for age.
    - Decrease in height SD by more than 0.5 over 1 year in children over 2 years old.
  4. Poor Growth Rate Without Short Stature:
    - Growth rate more than 2 SD below the average over 1 year.
    - Growth rate more than 1.5 SD below the average sustained over 2 years.
  5. Signs of Brain Issues: Symptoms indicating a possible brain lesion.
  6. Multiple Hormone Deficiencies: Signs of deficiencies in multiple pituitary hormones.
  7. Neonatal Symptoms: Symptoms and signs of GHD present at birth.
Diagnosis:
- Insulin-like Growth Factor 1 (IGF-1) & insulin-like growth factor binding protein 3 (IGF-BP3).
- GH-stimulating test: By clonidine and L-arginine
Treatment:
- Biosynthetic recombinant DNA-derived GH
Cushing syndrome:
- High cortisol level
- Height → below 3rd percentile
- Weight → normal or above normal
Loran syndrome:
- Tissue insensitivity to growth hormone due to GH receptor mutation
- Characteristics:
  - Microcephaly
  - Prominent forehead
  - Saddle nose
  - Hypoglycemia
  - Delayed puberty
  - Small genitalia
- Hormones: ↑ GH and ↓ IGF-1
Silver-Russell syndrome:
- Is a rare disorder characterized by IntraUterine Growth Restriction (IUGR).
- Clinical features:
  - ↓ Infant length
  - Relative macrocephaly
  - Dysmorphic facial features: asymmetric triangular face with a high forehead and drooping labial corner
  - Clinodactyly
  - Normal or mildly impaired cognitive development
NETCHINE-HARBISON Clinical Scoring System (you need 4 or more):
- Parameter: Yes - 1, No - 0
  - SGA
  - Postnatal growth failure
  - Relative macrocephaly
  - Fronte prominent
  - Asymmetry
  - Feeding difficulties or BMI < 2 SD
Labs:
- Complete Blood Count (CBC)
- Erythrocyte Sedimentation Rate (ESR)
- Thyroid-stimulating hormone (TSH)
- Tissue transglutaminase IgA (TTG IgA)
- Serum electrolytes including calcium and phosphorus
- Serum creatinine and bicarbonate levels
- Insulin-like Growth Factor 1 (IGF-1) & insulin-like growth factor binding protein 3 (IGF-BP3)
- Chromosome analysis
- Radiographic studies to Bone age determination
  - Bone Age = Chronologic Age: Familial short stature, Turner syndrome, Intrauterine growth retardation, Skeletal dysplasia, Chronic diseases
  - Bone Age < Chronologic Age: Constitutional short stature, Hypothyroidism, Hypercortisolism, Growth hormone deficiency

Pancreas & Diabetes Mellitus

Beta cells secrete insulin.
Function of insulin:
- Take the glucose from the blood & take it inside the cell
- Anabolic hormone
Type 1 DM:
- Most common in the pediatric age group.
- Not related to obesity
- Genetic predisposition is weak.
- Cause is Autoimmune that destroys the beta cells → no insulin in the body → hyperglycemia:
  - Environmental triggers e.g. viral, diet
  - Autoantibody:
    - Islet Cell Antibodies (ICA) → sensitivity 70 – 80%
    - Glutamic Acid Decarboxylase 65 (GAD65) → sensitivity 70 – 80%
    - Insulinoma‐Associated Antigen‐2 (I‐A2, ICA512) → sensitivity 60%
    - Anti-insulin (IAA) → sensitivity 60 – 80%
    - Zinc Transporter 8 (ZnT8) → sensitivity 60%
- Risk of developing Type 1 DM:
  - General population → 0.4%
  - Children with no autoantibodies → 0.4%
  - Children with one autoantibody → 14.5%
  - Children with multiple autoantibodies → 70%
  - Offspring of an affected mother → 1 to 4%
  - Offspring of an affected father → 3 to 8%
  - Offspring with both parents affected → 30%
Symptoms & presentation:
- Polyuria → cause hypokalemia
- Polydipsia
- Polyphagia
- Nocturia
- Weight loss or lack of weight gain, with poor gain in height
- Fatigue
- Blurred vision.
- Candidal nappy rash is common in infants
- Vulvar/vaginal candidal infections in school‐age and teenage girls

Diagnosis: Glucose Test

	Impaired glucose tolerance "pre-diabetic" (mg/dL)	DM (mg/dL)
Random plasma	-	>200 with diabetic symptoms
Fasting	110-126	>126 on 2 occasions
2-hour postprandial	140-200	>200 on 2 occasions
HemoglobinA1c (%) for monitoring	5.7-6.4	>6.5

Management & Therapies:

Insulin replacement therapy
Establishing an initial nutritional plan
Teaching the young person and their family/carers initial survival skills, including:
- Insulin injections
- Self Blood Glucose Monitoring (SBGM) → 4-6 times daily
- Hypoglycemia management

Diabetic KetoAcidosis:
- Is a serious and life‐threatening disorder
- Results from absolute or relative insulin deficiency & Counter‐regulatory hormones are markedly ↑: Glucagon, cortisol, catecholamines, and growth hormone.
- Resulting in a catabolic state:
  - Increased glucose production (gluconeogenesis and glycogenolysis) → Hyperglycemia
  - Increased lipolysis and ketogenesis → ketonemia & wide anion gap metabolic acidosis.
- Criteria for the diagnosis of DKA are:
  - Hyperglycaemia (Blood Glucose concentration >11 mmol/L).
  - Venous pH < 7.3 or bicarbonate <18 mmol/L.
  - Ketonemia and ketonuria
Clinical manifestations of diabetic ketoacidosis:
- Dehydration
- Tachypnea → deep & rapid respiration (Kussmaul)
- Nausea, vomiting, and abdominal pain that may mimic an acute abdominal condition
- Confusion, drowsiness & loss of consciousness
Management of DKA:
- Correct dehydration: Should begin before starting insulin therapy.
- Insulin therapy Begin with:
  - Give a low dose of insulin to prevent cerebral edema = 0.05 to 0.1 U/kg/h regular insulin at least 1 hour after starting fluid replacement therapy
  - When the glucose returns to normal → give glucose with insulin to prevent hypoglycemia
  - Insulin:
    - Activate the cell to take the glucose → ↓ blood glucose
    - Activate Na+/K+ pump → Cause hypokalemia
    - If K+ is <3.3mEq/L → hold insulin & give 20 to 30 mEq/hr until K+ reaches 3.3 – 5.2
- Bicarbonate : Given if pH <6.9

Rickets & Vitamin D Metabolism

Vitamin D metabolism:

Parathyroid hormone & calcitonin:

	ParaThyroid Hormone	Calcitonin
Secreted by	Parathyroid hormone	Cells (parafollicular cells) of the thyroid gland
Function	↑ Ca2+ reabsorption & ↓ PO43– reabsorption in the kidney Bone resorption → ↑ Ca2+ & PO4 3– Stimulate the 1 alpha hydroxylase enzyme in the kidney → increase Vitamin D3 synthesis.	Decrease the calcium in the blood by Increases the deposition of calcium into bone
Secretion increase by	Decrease in free calcium	Increase in free calcium
Secretion decrease by	Increase in free calcium	Decrease in free calcium

Rickets:

New bone formation is defective & there is minerals deficiency
Predisposing factors:
- Exclusively breastfed infants with minimal sunshine exposure
- Use of anticonvulsant medications (phenytoin, phenobarbital), which interfere with liver metabolism
- Renal or hepatic failure
Clinical features:
- Usually occurs during the first 2 years of life and in adolescence, when bone growth is most rapid.
- Rickets usually involves the wrists, knees, and ribs, presenting with a knobby appearance.
  - "Rachitic rosary” → prominent costochondral junctions
- Weight-bearing bones become bowed
- Short stature
- Craniotabes or thinning of the outer skull:
  - “Ping-Pong ball sensation” on palpation - Earliest sign of rickets
- Frontal bossing and delayed suture closure
Etiology:
- The most common cause of hypocalcemia → malnutrition
- Vitamin D deficiency
- GI disorders associated with fat malabsorption resulting in vitamin D deficiency (cystic fibrosis, celiac disease)
- Nutritional causes
- Defective vitamin D metabolism from renal & hepatic failure: Cause a deficiency of the important enzymes that synthesize 1,25-(OH) vitamin D
- Nutritional causes:
- Increased PTH → bone destruction → Increased alkaline phosphatase
- Low phosphate
- Low calcium
- Low 25 hydroxycholecalciferol
Vitamin D-dependent rickets:
- This autosomal recessive condition is rare.
- Enzyme deficiency in the kidneys of 1α-hydroxylase vitamin D results in the lack of 1,25-(OH) vitamin D.
- Patients present with:
  - Low vitamin D levels
  - Low calcium
  - Low phosphorus
  - Increased PTH → bone destruction → Increased alkaline phosphatase
Vitamin D-resistant rickets (X-linked hypophosphatemic rickets):
- X-linked dominant disorder
- Caused by a renal tubular phosphorus leak, resulting in a low serum phosphorus level
- Patients present with rickets in the face of normal calcium & low phosphorus.
- Patients develop typical bowing of the legs
- Treatment includes:
  - Phosphate supplements
  - 1,25 vitamin D analogues.
Radiographic findings:
- Wrist radiographs:
  - Show the earliest changes of rickets
  - There is widening of the space between the epiphysis and the end of the metaphysis
  - The distal end of the metaphysis appearing: Widened, frayed, and cupped
Condition: Calcium, Phosphate, PTH, 25(OH)D
- Primary hypoparathyroidism: ↓, ↑, ↓, Normal
- Pseudohypoparathyroidism: ↓, ↑, ↑, Normal
- Vitamin D deficiency: Normal, ↓, ↑, ↓
- Familial hypophosphatemic rickets: Normal, ↓, Normal, Normal
- Hyperparathyroidism: ↑, ↓, ↑, Normal

Adrenal Gland Diseases

Introduction to the adrenal gland:
- The Hypothalamic–Pituitary–adrenal Axis:
  1. Corticotropin-Releasing Hormone (CRH):
    - Released from the hypothalamus
    - Activates the anterior pituitary
  2. AdrenoCorticoTropic Hormone (ACTH):
    - Released from the anterior pituitary
    - Activates the adrenal gland cortex
- Adrenal gland:
  | Layer | Hormone class | Function |
  | :--------------- | :--------------- | :----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
  | Cortex | Zona Glomerulosa | Mineralocorticoids - Regulate salt retention & blood pressure |
  | | Zona fasciculata | Glucocorticoids - Contribute to many metabolic processes & are needed for the maintenance of blood glucose & wellbeing |
  | | Zona Reticularis | Androgens - Influence androgen dependent hair growth |
  | Medulla | Chromaffin cell | Catecholamine - Needed for an acute stress response (sympathetic) |
- Cortisol:
  - Causes negative feedback inhibition of pituitary & hypothalamus
  - Increases glucose in the blood
- Aldosterone:
  - Causes reabsorption of sodium & excretion of potassium & H+ in kidney tubules
- The diseases in adrenal gland could be because problem in:
  - Primary → adrenal gland
  - Secondary → pituitary gland
  - Tertiary → hypothalamus
Congenital Adrenal Hyperplasia:
- Autosomal recessive disease
- Most common cause is Mutation in CYP 21A2 gene → 21‐Hydroxylase (P450c21) deficiency: This deficiency causes impaired synthesis of aldosterone & cortisol
- This results in:
  - Loss of negative feedback → hyperplasia
  - High ACTH → hyperpigmentation
  - Low cortisol → Hypoglycemia
  - No aldosterone:
    - Hyponatremia → cause low blood pressure
    - Hyperkalemia
    - Metabolic acidosis
  - In the 46,XY male fetus with 21‐hydroxylase deficiency:
    - The excess of adrenal androgens in boys does not seem to have an additional phenotypic effect
  - In the 46,XX fetus with 21‐hydroxylase deficiency:
    - The excess of adrenal androgens in girls causes virilization of the external genitalia (ambiguous genitalia)
Hypoaldosteronism (addison disease):
- Cause hyperchloremic hyperkalemic metabolic acidosis
Standard-dose ACTH stimulation test (cosyntropin test):
- Gold standard to confirm the diagnosis of primary adrenal insufficiency
- Method:
  - Administration of exogenous ACTH to stimulate cortisol secretion
  - Physiological response: exogenous ACTH → ↑ cortisol
  - In primary adrenal insufficiency: peak cortisol level < 18–20 μg/dL (< 500–550 nmol/L)
  - In secondary/tertiary adrenal insufficiency: usually a rise in cortisol > 18–20 μg/dL (> 500–550 nmol/L)
Enzyme deficiency Mineralocorticoids [K+] Blood pressure Cortisol Sex hormones Labs Presentation
- 17α- hydroxylase ↑ ↓ ↑ ↓ ↓ ↓ androstenedione
  - XY: atypical genitalia, undescended testes
  - XX: lacks 2° sexual development
- 21- hydroxylase ↓ ↑ Normal or ↓ ↓ ↑ ↑ 17-hydroxyprogesterone XX: virilization
- 11β- hydroxylase ↓ aldosterone ↑ 11-deoxycorticosterone ↓ ↑ ↓ ↑
  - Presents in infancy (severe hypertension) or childhood (precocious puberty)
  - XX: virilization
Cushing Syndrome:
- A metabolic disorder caused by overproduction of corticosteroid hormones by the adrenal cortex (high serum cortisol)
- Causes:
  - Iatrogenic exogenous glucocorticoid administration remains the most common cause of CS
  - Cushing disease: ACTH pituitary adenoma
- Clinical feature:
  - Growth failure and weight gain
  - Cushingoid appearance with ‘moon facies’.
  - Hirsutism, acne, facial plethora, and striae.
  - Psychological disturbances, hypertension, headaches, and fatigue.
- Investigation of Cushing disease:
  - Hyperglycemia
  - 24-hour urine collections for Urinary Free Cortisol
  - Determination of midnight cortisol in the sleeping child (normally less than <50 nmol/L).
  - Dexamethasone suppression test:
    1. Low dose:
      - Suppresses cortisol in normal individuals
      - Fails to suppress cortisol in all causes of Cushing syndrome
    2. High dose:
      - Suppresses ACTH Production by pituitary adenoma
      - Fails to suppress ACTH by ectopic production
- Treatment (according to the cause):
  - Medical therapy to lower cortisol using metyrapone, ketoconazole, or etomidate is useful for short‐term

Thyroid Gland Diseases

The Hypothalamic–Pituitary–Thyroid Axis:
- Thyroid Releasing Hormone (TRH):
  - Released from the Hypothalamus
  - Binds to TRH receptor in the pituitary gland → Activated pituitary gland to secrete TSH
- Thyroid Stimulating Hormone (TSH):
  - Released from the anterior pituitary gland
  - Binds to the thyroid gland → activating the thyroid gland to secrete Thyroid hormone (T4 & T3)
Function of thyroid hormone:
- Brain maturation
- Bone growth (synergism with GH and IGF-1)
- ↑ β1 receptors in heart → ↑ CO, HR, contractility
- Basal metabolic rate
- Blood sugar (↑ glycogenolysis, gluconeogenesis)
- Break down lipids (↑ lipolysis)
- Stimulates surfactant synthesis in Babies
The diseases in the thyroid gland could be because problem in: Primary: Thyroid, Secondary: Pituitary, Tertiary: Hypothalamus
- Hypothyroidism:
  - TSH: High, Normal or low, Normal or low
  - T3 & T4: Low, Low, Low
- Hyperthyroidism:
  - TSH: Low, Normal, High
  - T3 & T4: High, High, High
Congenital Hypothyroidism (cretinism):
- Is the commonest neonatal endocrine
- Not easily diagnosed
- Clinical presentation:
  - Suboptimal growth velocity with a delayed bone age
  - Goiter may sometimes be detected on palpation of the thyroid.
  - Myxedema, or “puffy skin,” dry skin
  - Amenorrhea or oligomenorrhea in adolescent girls
  - Fatigue or decreased energy levels
  - Constipation
  - Mental retardation → preventable if the treatment start early
  - Tongue protrusion
  - Umbilical hernia
  - Large anterior fontanelle
- Etiology:
  - Thyroid ectopy (most common): Abnormally located thyroid gland accounting for 50–60% of CH
  - Thyroid agenesis
- Newborn screening for congenital hypothyroidism is based on a heel prick capillary blood spot TSH taken between 2 & 4 days
- Treatment:
  - Levothyroxine: Should start as early as possible and usually on the day of diagnosis. The dose administered is between 10 and 15 μg/kg
    - If the treatment is delayed:
      - Intellectual performance will not return to normal
      - Tongue protrusion, growth & bone age will return to normal
  - Babies should be reviewed every 1–2 weeks until euthyroidism is achieved and then 1–2 monthly
Hashimoto’s thyroiditis (hypothyroidism):
- Autoimmune disease that causes destruction of the thyroid gland by lymphocytes
- Is the most common acquired thyroid disease of childhood.
- On ultrasound → typical hypoechoic area within the thyroid gland.
- More in patients with Down or Turner syndrome and with other autoimmune diseases like DM type1
- Goiter
- Diagnosis:
  - The diagnosis may be confirmed by serum antithyroid peroxidase (previously antimicrosomal) & antithyroglobulin antibodies.
  - Lab:
    - Raised TSH
    - Low free T4
- Treatment:
  - Levothyroxine should be initiated at a low dose and increased slowly to therapeutic doses
Graves Disease:
- It is caused by the presence of Thyrotropin receptor antibodies:
  - Is antibodies act on the TSH Receptor, leading to hyperstimulation of the thyroid gland → Goiter
- Is the most common cause of hyperthyroidism in children.
- It is seen most often in girls in the 10–15 year age group.
- Presentation is often delayed, particularly in the younger child.
- Symptoms:
  - Restlessness
  - Agitation
  - Poor concentration
  - Deteriorating school performance is often reported.
  - Headache
  - Tachycardia
  - Difficulty in sleeping
  - ↑ in growth velocity, weight loss, and advance of bone age.
- Thyroid eye disease:
  - Exophthalmos
  - Lid lag
  - Lid retraction
- Lab:
  - Suppressed TSH
  - Raised free T4 and T3.
  - Thyroid peroxidase and Thyrotropin receptor antibodies can coexist
  - In some cases, antibodies are not initially detected
- Management:
  - Initial management is aimed at achieving euthyroid status
  - Propranolol (beta blocker) is a useful adjunct at presentation to provide symptomatic relief
  - Antithyroid Drugs: Methimazole & PTU
  - Thyroidectomy
  - Radioactive iodine is considered safe and effective for those over the age of 10 years
Subclinical hypothyroidism:
- Thyroid hormone: Normal
- TSH: TSH
Subclinical hyperthyroidism:
- Thyroid hormone: Normal
- TSH: ↓