34 years of journey

in UMMC

Dr Noor Lita Adam260609

• 1975-1980:• 6 year old boy was referred for goitre• Clinically euthyroid, no family history of thyroid disorder• Antenatal/developmental – normal• Height: below 10th centile, weight: at 10th centile• Diffuse, soft goitre- 3x2 cm• Ix:

– Protein: 6.6g/100ml– Albumin: 3.8g/100ml– Cholesterol: 17.5 mg/100 ml– PBI: 5.3 g/100 ml– ESR; 8 mm/hr

• IMPRESSION: non-toxic goitre• Management:

– L-thyroxine 100 mcg od ? Early Hashimoto’s goitre regressed– Trial stopping thyroxine- goitre recurred thyroxine restarted– Dose increased to 150 mcg od- ht < 3rd centile, poor school performance

(26th place in class)

• 1980-1990• Thyroxine continued• TFT monitoring: T4: 5.4 (5-13 μg/100ml) T3-uptake: 27.2 (22.1-33.7%) T-7 (FTI): 1.47 (1.11-4.38)• Referred to adult 1986, age 17• Goitre increased in size after stopping thyroxine,

thyroid bruit+, tachycardia, hands tremor• Thyroid antibodies: microsomal: < 100,

thyroglobulin: 20, TSH: 17.9 uIU/ml (0.41-7.0)

RAI uptake and Perchlorate discharge test:RAI uptake and Perchlorate discharge test: 2H 2H 131131I thyroid uptake: 81%I thyroid uptake: 81% 1/2H 1/2H 131131I thyroid uptake post-perchlorate inj: 38%I thyroid uptake post-perchlorate inj: 38% 1H 1H 131131I thyroid uptake post-perchlorate inj: 32%I thyroid uptake post-perchlorate inj: 32% 11/2H 11/2H 131131I thyroid uptake post-perchlorate inj: I thyroid uptake post-perchlorate inj:

28%28% 2H 2H 131131I thyroid uptake post-perchlorate inj: 21%I thyroid uptake post-perchlorate inj: 21% A drop in excess of 50% of original value indicates A drop in excess of 50% of original value indicates

organification defect.organification defect. TFT:TFT:

T4: 98T4: 98 T3-uptake: 34T3-uptake: 34 T7 (FTI): 33T7 (FTI): 33

• 1990- till now

• On stable dose of L-thyroxine

• TFT: FT4/TSH- euthyroid, TSH: 0.7-3 iIU/ml

Congenital primary hypothyrodism

secondary organification defect

Fig. 2-2.: The iodide cycle. Ingested iodide is trapped in the thyroid, oxidized, and bound to tyrosine to form iodotyrosines in thyroglobulin (TG); coupling of iodotyrosyl residues forms T4 and T3. Hormone secreted by the gland is transported in serum. Some T4 is deiodinated to T3. The hormone exerts its metabolic effect on the cell and is ultimately deiodinated; the iodide is reused or excreted in the kidney. A second cycle goes on inside the thyroid gland, with deiodination of iodotyrosines generating iodide, some of which is reused without leaving the thyroid.

Inborn errors of thyroid hormonogenesis are responsible Inborn errors of thyroid hormonogenesis are responsible for 10-15% of neonatal hypothyroidism.for 10-15% of neonatal hypothyroidism.

A number of different defects have been characterized A number of different defects have been characterized and include:and include:

1) decreased thyrotropin (TSH) responsiveness1) decreased thyrotropin (TSH) responsiveness 2) failure to concentrate iodide2) failure to concentrate iodide 3) defective organification of iodide due to an 3) defective organification of iodide due to an abnormality in the peroxidase enzyme or in the abnormality in the peroxidase enzyme or in the HH22OO22 generating system generating system 4) defective thyroglobulin synthesis or transport4) defective thyroglobulin synthesis or transport 5) abnormal iodotyrosine deiodinase activity. 5) abnormal iodotyrosine deiodinase activity.

The association of an organification defect with sensorineural The association of an organification defect with sensorineural deafness is known as Pendred's syndrome. deafness is known as Pendred's syndrome.

Unlike thyroid dysgenesis, a sporadic condition, these inborn errors Unlike thyroid dysgenesis, a sporadic condition, these inborn errors of thyroid hormonogenesis tend to have an autosomal recessive of thyroid hormonogenesis tend to have an autosomal recessive form of inheritance consistent with a single gene mutation. It is not form of inheritance consistent with a single gene mutation. It is not surprising, therefore, that a molecular basis for many of these surprising, therefore, that a molecular basis for many of these abnormalities has now been identifiedabnormalities has now been identified. . These include mutations in These include mutations in the genes for the TSH receptor, sodium-iodide symporter, thyroid the genes for the TSH receptor, sodium-iodide symporter, thyroid peroxidase enzyme, and thyroglobulin, respectively; the gene for the peroxidase enzyme, and thyroglobulin, respectively; the gene for the iodotyrosine deiodinase enzyme has not been cloned to date.iodotyrosine deiodinase enzyme has not been cloned to date.

Pendred's syndrome has now been shown to be due to a defect in Pendred's syndrome has now been shown to be due to a defect in the pendrin gene on chromosome 7q22-31, a newly identified porter the pendrin gene on chromosome 7q22-31, a newly identified porter of iodide on the apical surface of the thyroid follicular cell with of iodide on the apical surface of the thyroid follicular cell with sequence homology to several sulfate transporters. sequence homology to several sulfate transporters.

Mutations in THOX2, important in hydrogen peroxide generation, Mutations in THOX2, important in hydrogen peroxide generation, have been shown recently to cause both transient and permanent have been shown recently to cause both transient and permanent forms of congenital hypothyroidism associated with a defect in forms of congenital hypothyroidism associated with a defect in organification.organification.