Congenital Hypothyroidism Screening & Levothyroxine, Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency), and Adrenal Crisis

Thyroid and Adrenal Disorders: Congenital Hypothyroidism, CAH, and Adrenal Crisis

Paediatric endocrinopathies affecting the thyroid and adrenal glands represent high-yield clinical entities on the European Board of Paediatrics (EBP-EAP) examination. Both congenital hypothyroidism and classic congenital adrenal hyperplasia are time-critical conditions: delayed recognition leads to irreversible intellectual disability or fatal circulatory collapse. Understanding the physiological feedback loops, newborn bloodspot screening programs, steroidogenesis pathways, and acute resuscitation algorithms is essential for clinical competence.

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Congenital Hypothyroidism: Screening, Etiology, and Management

Congenital hypothyroidism (CH) occurs in approximately 1 in 2,000 to 1 in 3,000 live births worldwide. Because thyroid hormones ($T_4$ and $T_3$) are indispensable for terminal arborization of neurons, synaptogenesis, and myelination in the developing brain, neonatal screening and prompt thyroxine replacement represent one of the greatest preventive triumphs of modern paediatrics.

Newborn Bloodspot Screening

• Screening Protocol: In most European countries, newborn bloodspot screening (Guthrie test) is performed on heel-prick capillary blood collected on filter paper between 48 and 72 hours of life.
• Biochemical Marker: The primary screening analyte is Thyroid-Stimulating Hormone (TSH). Testing after 48 hours avoids the physiological neonatal TSH surge that occurs immediately following birth.
• Cutoff and Confirmation: Elevated bloodspot TSH triggers urgent recall for confirmatory venous blood sampling (measuring free $T_4$ and TSH). An elevated venous TSH accompanied by low free $T_4$ confirms primary congenital hypothyroidism.

                 [ABNORMAL NEWBORN BLOODSPOT TSH]
                                |
                  [Confirm venous TSH and free T4]
                                |
       +------------------------+----------------------------+
       |                                                     |
 [High TSH + low free T4]                     [Normal free T4 + elevated TSH]
       |                                                     |
 [START LEVOTHYROXINE NOW]                    - TSH >20 mU/L: start treatment
 - Dose according to severity                - TSH 6-20 beyond 21 days:
 - Severe CH: 10-15 mcg/kg/day                  specialist review; treat or
 - Aim to start within 2 weeks                 retest in 1-2 weeks

Etiological Classification

Congenital hypothyroidism is classified into permanent and transient forms:

1. Thyroid Dysgenesis (85% of permanent cases):
   • Abnormal embryological development or migration of the thyroid gland. Typically sporadic.
   • Ectopic Thyroid (60%): Incomplete caudal migration; thyroid tissue rests along the thyroglossal tract, most commonly at the base of the tongue (lingual thyroid). Represents the single most common cause of CH.
   • Athyreosis / Aplasia (20%): Complete absence of thyroid tissue.
   • Hypoplasia (5%): Rudimentary, underdeveloped gland.
2. Thyroid Dyshormonogenesis (15% of permanent cases):
   • Inborn errors of thyroid hormone biosynthesis, inherited in an autosomal recessive manner. Often presents with a goiter.
   • Defects in TPO, TG or DUOX2 disrupt hormone synthesis; SLC5A5/NIS defects impair iodide transport.
   • Pendred Syndrome: Autosomal recessive mutation in SLC26A4 (pendrin transporter); features sensorineural hearing loss and goitre, usually with normal thyroid hormone levels.
3. Transient Hypothyroidism:
   • Caused by transplacental passage of maternal TSH-receptor-blocking antibodies (maternal Hashimoto thyroiditis), maternal exposure to antithyroid drugs (carbimazole, propylthiouracil), extreme prematurity, or perinatal exposure to excess iodine (topical povidone-iodine antiseptics) or severe iodine deficiency.
4. Central (Hypothalamic-Pituitary) Hypothyroidism (1 in 20,000):
   • Secondary to pituitary hypoplasia, septo-optic dysplasia, or isolated TSH deficiency. Characterized by low free $T_4$ with inappropriately normal or low TSH. Crucially, central hypothyroidism is missed by TSH-based screening programs.

Clinical Presentation of Missed Congenital Hypothyroidism

Because maternal thyroxine partially crosses the placenta during gestation, over 95% of newborns with CH appear normal at birth. Clinical manifestations emerge insidiously over the first several weeks of life:

Levothyroxine Replacement Protocol

• Dosing: Give oral levothyroxine once daily: 10–15 micrograms/kg/day for severe CH, about 10 for mild CH, and consider 5–10 when pretreatment free T4 is normal.
• Critical Timeframe: Treatment must be established strictly before 14 days of life to preserve normal intellectual quotient (IQ) and cognitive trajectory.
• Administration Technique: Tablets should be crushed and mixed with a few millilitres of breast milk or water on a small spoon. Do not mix with soy formula, iron, or calcium supplements, which chelate levothyroxine and severely impair intestinal absorption.
• Therapeutic Targets:
  • Serum free $T_4$ should rise into the upper half of the age-specific normal range within 1 to 2 weeks.
  • Serum TSH should normalize within 4 weeks and remain within the age-specific reference interval.
  • Check free T4 and TSH 1–2 weeks after starting, then every 2 weeks until TSH normalizes. Thereafter, check every 1–3 months to age 12 months, then every 2–4 months to age 3 years.

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Acquired Hypothyroidism in Children

In children beyond infancy and adolescents, the overwhelming majority of acquired hypothyroidism is caused by Hashimoto Thyroiditis (chronic lymphocytic thyroiditis / autoimmune thyroiditis).

Clinical Features and Diagnostics

• Pathophysiology: Autoimmune infiltration of the thyroid gland by cytotoxic lymphocytes, with production of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies.
• Hallmark Presentation: The single most sensitive clinical sign of acquired hypothyroidism in childhood is growth deceleration / growth arrest with relative preservation or increase in body weight (flattening of the height curve with rising BMI curve). Other signs include firm, non-tender goiter, sluggishness, cold intolerance, constipation, dry skin, and delayed bone age.
• Van Wyk-Grumbach Syndrome: Severe, long-standing juvenile hypothyroidism can paradoxically present with precocious puberty (breast development, galactorrhea, or testicular enlargement) accompanied by severe growth arrest. Markedly elevated circulating TSH levels act directly on gonadal FSH receptors due to structural glycoprotein hormone subunit homology.

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Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Congenital Adrenal Hyperplasia (CAH) encompasses a group of autosomal recessive disorders characterized by enzymatic defects in the adrenal steroidogenesis pathway leading to cortisol deficiency. Deficiency of 21-hydroxylase accounts for >90% to 95% of all CAH cases.

                                     [Cholesterol]
                                           |
                                     [Pregnenolone] --------> [17-OH Pregnenolone] --------> [DHEA]
                                           |                          |                          |
                                    [Progesterone]  --------> [17-OH Progesterone] -------> [Androstenedione]
                                           |                          |                          |
    [21-Hydroxylase (CYP21A2)] --------X---|--------------------------X---|                          |
    (ENZYMATIC BLOCK)                      |                          |                          V
                                 [11-Deoxycorticosterone]      [11-Deoxycortisol]           [TESTOSTERONE]
                                           |                          |                     (ANDROGEN EXCESS)
                                    [Corticosterone]              [Cortisol]
                                           |                          |
                                     [ALDOSTERONE]             [DEFICIENT CORTISOL]
                                   (SALT WASTING)                     |
                                                              [Loss of Feedback]
                                                                      |
                                                                 [MASSIVE ACTH]
                                                                      |
                                                        [Adrenal Cortical Hyperplasia]

Molecular Genetics and Pathophysiology

• Gene Locus: Mutations, microdeletions, or gene conversions in the CYP21A2 gene located on the short arm of chromosome 6p21.3 within the HLA complex. The presence of a non-functional pseudogene (CYP21A1P) predisposes to unequal crossing-over during meiosis.
• The Biochemical Block:
  • Inability to convert Progesterone to 11-deoxycorticosterone (aldosterone pathway).
  • Inability to convert 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol (cortisol pathway).
• Downstream Consequences:
  1. Cortisol Deficiency: Absence of circulating cortisol removes negative feedback inhibition at the hypothalamus and anterior pituitary, triggering massive secretion of Adrenocorticotropic Hormone (ACTH).
  2. Adrenal Hyperplasia: Sustained high ACTH drives diffuse hyperplasia of the adrenal cortex.
  3. Adrenal Androgen Hypersecretion: Accumulated steroid precursor pools proximal to the block—predominantly 17-hydroxyprogesterone—are shunted into the active androgen pathway, generating excessive amounts of androstenedione, DHEA, and testosterone.
  4. Aldosterone Deficiency: Results in renal distal tubular inability to reabsorb sodium in exchange for potassium and hydrogen ions, producing severe renal salt-wasting, hyponatremia, hyperkalemia, and hypovolemia.

Clinical Phenotypes of 21-Hydroxylase Deficiency

Genital Manifestations and Chromosomal Sex

• 46,XX Virilization: In female fetuses, excessive adrenal androgens between 7 and 12 weeks of gestation virilize external genitalia, producing ambiguous genitalia at birth (Prader stages I to V): marked clitoromegaly, posterior labial fusion, scrotalization with hyperpigmentation, and a single urogenital sinus.
• Preserved Internal Female Anatomy: The uterus, cervix and fallopian tubes are Müllerian derivatives; the ovaries are separate gonadal structures. These organs develop normally in 46,XX CAH. Without fetal testicular AMH, Müllerian structures persist despite adrenal androgen excess.
• 46,XY Camouflage Hazard: Male neonates have entirely normal external genitalia at birth (with subtle scrotal hyperpigmentation). Consequently, in the absence of newborn bloodspot 17-OHP screening, affected 46,XY infants are discharged home undetected, only to collapse in the second or third week of life with catastrophic salt-wasting shock.

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Neonatal Adrenal Crisis and Long-Term Maintenance

The Salt-Wasting Crisis (Days 7 to 21 of Life)

An infant with classic salt-wasting CAH who is untreated typically presents between day 7 and day 21 with acute adrenal crisis:

• Poor feeding, failure to regain birth weight, faltering growth
• Recurrent projectile vomiting (frequently misdiagnosed as pyloric stenosis)
• Dehydration, mottled extremities, prolonged capillary refill, hypovolemic shock
• Electrolyte hallmarks: Profound hyponatremia ($<130\text{ mmol/L}$), severe hyperkalemia ($>6.5\text{--}8.0\text{ mmol/L}$), hypoglycemia, and normal or elevated anion gap metabolic acidosis.

Emergency Adrenal Crisis Resuscitation Algorithm

                    [SUSPECTED ADRENAL CRISIS: TREAT IMMEDIATELY]
                                      |
             +------------------------+-------------------------+
             |                                                  |
 [RESTORE CIRCULATION / GLUCOSE]                     [GIVE HYDROCORTISONE IV/IM]
 - 0.9% saline 10 mL/kg promptly                     - Initial emergency dose by age:
 - Reassess; repeat for persistent shock               <1 year: 25 mg
 - If glucose <3 mmol/L: D10 2 mL/kg IV                 1-5 years: 50 mg; >=6 years: 100 mg
 - Recheck glucose after 15 minutes                  - THEN continue stress-dose treatment
 - Follow sodium and fluid balance                    by infusion or divided IV doses

1. Intravenous Volume and Glucose Resuscitation:
   • Give 0.9% saline 10 mL/kg promptly for shock, reassess circulation and repeat if needed.
   • If glucose is <3 mmol/L, give 10% dextrose 2 mL/kg IV separately; recheck after 15 minutes and repeat if still low.
   • Continue glucose-containing maintenance fluid as needed. Check sodium frequently: hydrocortisone and saline can raise it rapidly. Limit the rise to 10 mmol/L in 24 hours.
2. Immediate Stress-Dose Hydrocortisone:
   • Give an immediate IV/IM hydrocortisone loading dose: emergency age-based doses are 25 mg under 1 year, 50 mg at 1–5 years, and 100 mg at ≥6 years. Then continue parenteral stress dosing; the Endocrine Society regimen uses 50–100 mg/m²/day, by infusion or divided every 6 hours.
   • Mineralocorticoid note: Exogenous fludrocortisone is NOT required during acute crisis resuscitation; high-dose hydrocortisone provides sufficient cross-reactivity at the mineralocorticoid receptor, and intravenous saline re-expands extracellular volume.
3. Hyperkalemia Management:
   • In most cases, volume expansion and hydrocortisone normalize potassium.
   • If electrocardiogram shows hyperkalemic toxicity (peaked T waves, widened QRS, flattened P waves), administer 10% Calcium Gluconate (0.5 mL/kg IV over 5–10 minutes) to stabilize the myocardium, followed by salbutamol nebules or IV glucose-insulin infusion.

Long-Term Replacement Therapy

Once stable, children require triple therapy tailored to suppress excess adrenal androgens while maintaining physiological glucocorticoid and mineralocorticoid activity:

1. Glucocorticoid Replacement:
   • Oral Hydrocortisone at 10 to 15 mg/m2/day, divided into three doses daily. The morning or evening dose may be increased to optimize diurnal ACTH suppression.
   • Synthetic glucocorticoids (dexamethasone, prednisolone) are avoided in growing children due to excessive growth suppression.
2. Mineralocorticoid Replacement:
   • Oral Fludrocortisone at 0.05 to 0.2 mg/day (single or twice-daily dose) to normalize serum sodium, potassium, and plasma renin activity.
3. Sodium Chloride Supplementation in Infancy:
   • Infants have physiological renal resistance to mineralocorticoids and consume breast milk or infant formula containing minimal sodium. Oral NaCl 1–2 g/day (17–34 mmol/day) is usually needed in early infancy. Reassess the dose and continuing need using blood pressure, sodium, potassium and renin as renal function and diet mature.

Sick-Day Management Rules

During periods of physiological stress (pyrexia $\ge 38.5^\circ\text{C}$, physical trauma, general anaesthesia), endogenous cortisol requirements increase three- to five-fold. Parents must be educated on "sick-day rules":

• Febrile or clinically significant illness: Follow the child’s sick-day plan, commonly double or triple oral hydrocortisone while unwell. A mild cold or runny nose without fever usually needs no dose increase.
• Severe Illness, Persistent Vomiting, or Lethargy: Administer intramuscular (IM) Hydrocortisone immediately (25 mg under 1 year, 50 mg at 1–5 years, 100 mg at ≥6 years) and proceed to the nearest emergency department immediately.
• Fludrocortisone: Does not need to be increased during sick days.