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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
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