Thyroid disorders in childhood

and adolescence

Fergus Cameron

Royal Children’s Hospital, Melbourne

• Thyroid physiology

• Iodine deficiency

• Congenital hypothyroidism

• Transient disorders of thyroid function in infancy

• Hyperthyroidism

• Hypothyroidism

• Thyroid Masses

Thyroid physiology

• Thyroid gland traps serum iodide with a

gradient of 30-40:1

• Iodide oxidised to iodine

• Organification (iodination of thyroglobulin-

bound tyrosyl residues to form MIT and DIT

• Thyroid peroxidase couples the iodotyrosines

to form T4 and T3 (T4:T3 synthesis rate is

10-20:1, release rate is 3:1)

Copyright ©2005 BMJ Pubishing Group Ltd.

Park, S M et al. J Med Genet 2005;42:379-389

Schematic diagram of a follicular cell, illustrating the steps involved in thyroid hormone synthesis. TSH receptor (TSHR) bound to TSH stimulates iodide transport into the thyroid gland by the sodium iodide symporter (NIS). Subsequently, iodide is oxidised by

hydrogen peroxide, generated by the recently discovered NADPH oxidase system (ThOX) and bound to tyrosine residues in thyroglobulin (TG) to form iodotyrosine (iodide organification). Some of these hormonally inactive iodotyrosine residues

(monoiodotyrosine and diiodotyrosine) couple to form the hormonally active iodothyronines, T4 and T3. Thyroid peroxidase (TPO) catalyses the oxidation, organification, and coupling reactions. The exact function of pendrin, a chloride-iodide transporter, in

thyroid hormone synthesis is as yet unknown but it is thought to transport iodide into the colloid from the thyrocyte. Defects in any of these steps lead to dyshormonogenesis, which manifests clinically as congenital hypothyroidism with goitre.

Thyroid physiology

• 80% of circulating T3 results from peripheral

deiodination of T4

• T3 binds to nuclear receptor with 10 times the

affinity of T4

• Regulate gene transcription increasing

cytoplasmic proteins which stimulate

mitochondrial activity

Worldwide, iodine deficiency remains the leading cause of

developmental delay in childhood

1,709 late primary school-aged children, mainland Australia,

Overall median UIE = 104ugm/l, borderline deficient

Creswell et al Med J Aust 2006; 184:165-9

Thyroid disorders in infancy

• Congenital hypothyroidism

• Transient disturbances in thyroid

function

Congenital hypothyroidism

• 1 in 3-5,0000 births

• 85% due to dysgenesis (agenesis, ectopia)

• 10% due to dyshormonogenesis

• 5% due to hypothalamic/pituitary failure

Normal thyroid scan

Ectopic thyroid scan

Agenic thyroid scan

Dyshormonogenic goitre

Molecular pathogenesis of

congenital hypothyroidism

• DYSHORMONOGENESIS:

Mutations in thyroid peroxidase (TPO),

thyroglobulin (TG), sodium iodide

transporter (NIS), chloride iodide transporter

(pendrin), TSH-receptor and thyrotropin-related

genes.

• DYSGENESIS:

Mutations in transcription factors (TTF-1, TTF-2

and Pax-8)

Molecular pathogenesis of

congenital hypothyroidism

Gene Thyroid Associated

mutation phenotype malformations

TPO Dyshorm. Nil

TG Dyshorm. Nil

NIS Dyshorm.* Nil

Pendrin Dyshorm.*/ Congenital

euthyroid deafness,

goitre mental delay

* Thyroid gland not seen on isotope scanning, present on U/S

Gene Thyroid Associated

mutation phenotype malformations

TSH-receptor Variable Nil

Dyshorm.*/

Incr. TSH,

normal T3/T4

Thyrotropin Secondary Mental delay,

(Pit-1, Prop-1 hypothyroidism midline malform’n

HesX-1, TRH- syndromes

receptor)

* Thyroid gland not seen on isotope scanning, present on U/S

Molecular pathogenesis of

congenital hypothyroidism

Molecular pathogenesis of

congenital hypothyroidism

Gene Thyroid Associated

mutation phenotype malformations

TTF-1/ Normal Respiratory distress,

NKX2.1 Hypoplasia chronic lung disease,

Ageneisis mental delay

choreoathetosis

TTF-2 Hypoplasia/ Choanal atresia,

ectopia spiky hair, cleft palate

Pax-8 Hypoplasia/ Renal malformation,

ectopia cryptorchidism

Transient disturbances in infantile

thyroid function

• Transient hypothyroxinaemia

• Transient primary hypothyroidism

• Transient hyperthyrotropinaemia

• Low T3/T4 syndrome (“sick euthyroid”)

Transient hypothyroxinaemia

• Low serum T4 levels seen in approx.

50% of infants delivered before 30 weeks

gestation

• Normal or low TSH levels

• Corrects spontaneously over 4-8 weeks

• No Rx required

Transient primary hypothyroidism

• Low serum T4 levels and high TSH levels

seen in approx. 20%of premature infants

(incidence increases as gestation decreases)

• Usually develops within 1-2 weeks ex-utero

and often superimposed upon transient

hypothyroxinaemia

• Hypothyroidism may persist for 2-3months

• Rx recommended

Transient hyperthyrotropinaemia

• Rare (1 in 16-19,000 births)

• Elevated TSH for 3-9 months before

reducing spontaneously

• No Rx required but need careful follow-up

to exclude partial dyshorm. or ectopia

Low T3/T4 syndrome (“sick euthyroid”)

• Non-thyroidal illness

T3 T4 TSH

Low T3 syndrome N N

Low T4 syndrome N

• No Rx required

Transient disturbances in infantile

thyroid function

Serum levels of: Aetiology

T4 TSH

Transient N Immaturity of H-P

hypothyroxinaemia axis (<30 wks gest’n)

Transient primary Maternal anti-

Hypothyroidism thyroid therapy,

iodine def.,

maternal Ab’s,

ideopathic

Transient disturbances in infantile

thyroid function

Serum levels of: Aetiology

T4 TSH

Transient N Erroneous assay,

hyperthyrotropinaemia iodine def. or

excess, idiopathic

Low T3/T4 syndrome N N Prematurity,

In preterm infants or surgical stress,

sepsis,

malnutrition

Hyperthyroidism

Congenital

• 1-2 cases per 1,000 pregnancies have maternal

thyrotoxicosis

• Of these 1 in 70 result in neonatal disease

• Transplacental passage of TSH-receptor Ab’s

• Signs of thyrotoxicosis as well as jaundice,

hepatosplenomegaly

• Rx: with antithyroid drugs +/- beta blockade

• May last up to 12 weeks

Hyperthyroidism

Acquired

• Females affected 6-8 times more frequently than males

• Graves disease, toxic Hashimoto’s disease (transient),

toxic nodule (rare)

• Signs of thyrotoxicosis may be subtle

• 30% have associated TED

• Ix: TFT’s, anti-thyroid receptor Ab’s, thyroid ultrasound

• Rx: CBZ +/- beta blockade for initial 2-4 weeks

• 20-50% spontaneous remission after 2 years

• If no remission options include radioablation, surgery

or ongoing medical Rx (PTU only in pregnancy)

Rivkees et al. N Engl J Med 2009, April 9

• PTU has advantages over methimazole/carbimazole in:

1) pregnancy (Methimazole associate with an

18 fold risk of choanal atresia and 0.03%

aplasia cutis)

2) T3 toxicosis

• 40% paediatric patients in the US with hyperthyroidism have

been treated with PTU

• PTU-induced liver failure may occur at a rate of 1 in 2-4,000 children (case reports requiring liver transplantation)

• Reversible PTU-induced liver damage is estimated at 1 in 200 (0.1% in adults)

• Unpredictable latency after initiation of treatment (days to years)

• Monitoring of LFT’s has not been shown to decrease risk of severe liver dysfunction

Therefore PTU should NOT be used as a first line

anti-thyroid drug in hyperthyroidism

Possible exceptions:

Pregnancy (1st trimester only then switch to methimazole/

carbimazole)

Severe reaction to methimazole/carbimazole and either

surgery or radiotherapy is not an option

ENDORSED BY THE US ENDOCRINE SOCIETY

(April 14, 2009)

Hypothyroidism

Acquired • Uncommon in iodine replete areas

• Primary (autoimmune/Hashimoto’s thyroiditis)

• Secondary (pituitary/hypothalamic pathology)

• High dose iodine exposure (Wolff-Chaikov effect)

• Radiation (Ca risk)

• Clinical triad of growth retardation, obesity, mental dullness

• Ix: TFT’s, Thyroid anti-TPO and anti- TBG Ab’s,

other Ix as indicated (MRI pituitary etc)

• Rx: T4 50-100ugm/day

(A) Normal

(B) Graves disease:

diffuse increased uptake in

both thyroid lobes.

(C) Toxic multinodular

goiter (TMNG): “hot”

and “cold” areas of uneven

uptake.

(D) Toxic adenoma:

increased uptake in a

single nodule with

suppression of the

surrounding thyroid.

(E) Thyroiditis: decreased

or absent uptake.

Wolff-Chaikov effect

• Quantity of iodine undergoing organification shows a

biphasic response to dose of iodide

• Firstly increasing and then decreasing due to relative

blockade of organic binding

• The second phase is known as the Wolff-Chaikov

effect

• Mechanism of inhibition of organification:

– High iodide conc’n reducing TPO-catalyzed organification

– Formation of inhibitory iodolipids within thyroid cells

Wolff-Chaikov effect

• Goitre and hypothyroidism can result

• In normal thyroid there is an escape mechanism of

decreased iodide transport into the cell via decreased

NIS expression (not present in 3rd trimester foetus’,

so they are at risk of WC if Mo takes high dose iodide

during pregnancy)

• Greater susceptibility to WC if:

– Stimulation of iodide-trapping mechanism (Grave’s

disease, excess TSH stimulation)

– Underlying impairment of organification

(Hashimoto’s, previous irradiation)

Thyroid masses

Goitre• 4-5% of all children (more common in peri-pubertal girls)

• Asymptomatic, hyper- or hypo-functioning

• Pressure effects rare

• Thyroid tenderness occasionally with thyroiditis

• Ix U/S, TFT’s, Ab’s

• Rx Correct thyroid status, observe

Thyroid masses

Thyroid nodules• Single or multiple

• <2% of children have thyroid nodules, of these approx.

2% are malignant

• Increased risk of malignancy (30-40%) if single nodule

• Cysts, cystic adenomas, adenomas

• Malignancies: Papillary/mixed> follicular> medullary>

anaplastic carcinomas

• 80% of malignant nodules have a history of radiation

exposure

• Ix: U/S, Nuclear scan, TFT’s , Ab’s, calcitonin, TBG, fine

needle or open excision biopsy

• Rx: Observe, surgery and I131 ablation with

TSH suppression

MEN 2/RET oncogene mutation

• MEN 2A: Medullary thyroid carcinoma (>90%), parathyroid hyperplasia (15-20%), phaeochromocytoma(50%)

• MEN 2B: Medullary thyroid carcinoma (>90%), phaeochromocytoma (50%)

• Familial medullary thyroid carcinoma (FMCT), (>90%)

Conclusions

• Thyroid disorders are common in childhood and

adolescence:

– < 5 yrs Transient thyroid disorders, congenital

hypothyroidism

– 1-10 yrs Congenital hypothyroidism

– >10 yrs autoimmune thyroid disease

– Thyroid malignancies are rare