34 years of journey in UMMC Dr Noor Lita Adam

: 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)

Thyroxine continued TFT monitoring: T4: 5.4 (5-13 μg/100ml) T3-uptake: 27.2 ( %) T-7 (FTI): 1.47 ( ) 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 ( )

RAI uptake and Perchlorate discharge test: RAI uptake and Perchlorate discharge test: 2H 131 I thyroid uptake: 81% 2H 131 I thyroid uptake: 81% 1/2H 131 I thyroid uptake post-perchlorate inj: 38% 1/2H 131 I thyroid uptake post-perchlorate inj: 38% 1H 131 I thyroid uptake post-perchlorate inj: 32% 1H 131 I thyroid uptake post-perchlorate inj: 32% 11/2H 131 I thyroid uptake post-perchlorate inj: 28% 11/2H 131 I thyroid uptake post-perchlorate inj: 28% 2H 131 I thyroid uptake post-perchlorate inj: 21% 2H 131 I thyroid uptake post-perchlorate inj: 21% A drop in excess of 50% of original value indicates organification defect. A drop in excess of 50% of original value indicates organification defect. TFT: TFT: T4: 98 T4: 98 T3-uptake: 34 T3-uptake: 34 T7 (FTI): 33 T7 (FTI): 33

1990- till now On stable dose of L-thyroxine TFT: FT4/TSH- euthyroid, TSH: 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 T 4 and T 3. Hormone secreted by the gland is transported in serum. Some T 4 is deiodinated to T 3. 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 for 10-15% of neonatal hypothyroidism. Inborn errors of thyroid hormonogenesis are responsible for 10-15% of neonatal hypothyroidism. A number of different defects have been characterized and include: A number of different defects have been characterized and include: 1) decreased thyrotropin (TSH) responsiveness 1) decreased thyrotropin (TSH) responsiveness 2) failure to concentrate iodide 2) 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 H 2 O 2 generating system H 2 O 2 generating system 4) defective thyroglobulin synthesis or transport 4) defective thyroglobulin synthesis or transport 5) abnormal iodotyrosine deiodinase activity. 5) abnormal iodotyrosine deiodinase activity.

 The association of an organification defect with sensorineural deafness is known as Pendred's syndrome.  Unlike thyroid dysgenesis, a sporadic condition, these inborn errors of thyroid hormonogenesis tend to have an autosomal recessive form of inheritance consistent with a single gene mutation. It is not surprising, therefore, that a molecular basis for many of these abnormalities has now been identified. These include mutations in the genes for the TSH receptor, sodium-iodide symporter, thyroid peroxidase enzyme, and thyroglobulin, respectively; the gene for the iodotyrosine deiodinase enzyme has not been cloned to date.  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 of iodide on the apical surface of the thyroid follicular cell with sequence homology to several sulfate transporters.  Mutations in THOX2, important in hydrogen peroxide generation, have been shown recently to cause both transient and permanent forms of congenital hypothyroidism associated with a defect in organification.