Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 7. Thyroid disorders. Horm Res 2007;68(suppl 2):44 47
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1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 7. Thyroid disorders. Horm Res 2007;68(suppl 2):44 47 ESPE Code Diagnosis OMIM ICD10 7 THYROID DISORDERS 7A HYPOTHYROIDISM 1 7A.1 Congenital (primary) hypothyroidism (permanent) 2 Included: Late-onset hypothyroidism due to thyroid dysgenesis or dyshormonogenesis 7A.1a Disorders classified elsewhere: Secondary and tertiary hypothyroidism (6A.2) Thyroid hormone resistance (7E.3) 7A.1b Developmental defects/thyroid dysgenesis 3 7A.1b.1 Athyrosis/agenesis 4 # E03.1 7A.1b.2 Hypoplasia/hypogenesis 5 # E03.1 7A.1b.3 Ectopy 6 # Q89.2 7A.1c Inherited defects of thyroid hormone biosynthesis/thyroid E07.1 dyshormonogenesis 7 7A.1c.1 Iodine transport defect 8 # A.1c.2 Organification defects due to an abnormality in the TPO enzyme or in the H 2 O 2 generating system (includes Pendred syndrome) 9 # # # A.1c.3 Defective thyroglobulin synthesis or transport A.1c.4 Abnormal iodotyrosine deiodinase (dehalogenase) activity 11 % A.1d TSH-receptor defects/tsh unresponsiveness 12 # E07.9 # A.1y Other specified disorders 7A.1z Other disorders, unspecified 7A.2 Transient congenital hypothyroidism 7A.2a Iodine deficiency 13 E00 7A.2b Drug induced 7A.2b.1 Maternal anti-thyroid drug therapy 14 P72.2 7A.2b.2 Iodine excess due to iodinated contrast media P72.2 7A.2b.3 Iodine excess from other sources 15 P72.2 7A.2b.8 Other specified goitrogen P72.2 7A.2b.9 Other goitrogen, unspecified P72.2 7A.2c Maternal thyroid autoantibodies 16 P72.2 E
2 ESPE Code Diagnosis OMIM ICD10 7A.2d Thyroid dysfunction in prematurity (including transient P72.2 hypothyroxinaemia, transient primary hypothyroidism, transient hyperthyrotropinaemia, low T3 syndrome) 7A.2y Other specified disorder P72.2 7A.2z Idiopathic P72.2 % E06.3 7A.3 Acquired primary hypothyroidism 7A.3a Due to disorder classified elsewhere: Non-autoimmune thyroiditis (7E.4) 7A.3b Autoimmune thyroiditis/hashimoto s thyroiditis with decreased thyroid function 17 7A.3c Iodine deficiency 18 E01 7A.3d Iatrogenic 19 E89.0 7A.3d.1 Post-irradiation 7A.3d.2 Post-operative 7A.3e Iodine excess 20 7A.3f Drug-induced, including environmental conditions (goitrogens) 21 7A.3g Systemic diseases 22 E03.8 7A.3y Other specified disorders E03.8 7A.3z Idiopathic E03.9 7B HYPERTHYROIDISM 23 7B.1 Congenital hyperthyroidism (neonatal thyrotoxicosis) 24 7B.1a Disorders classified elsewhere: Isolated pituitary resistance to thyroid hormone (7E.3b) 7B.1b Maternal autoimmune thyroid disease 25 (neonatal Graves P72.1 disease) (usually transient) 7B.1c Activating TSH-receptor mutation 26 # E05.8 7B.1d G-protein mutations 27 E05.8 7B.1d.1 As part of McCune Albright [primary 14B.22] # E05.8 7B.1d.2 Other E05.8 7B.2 Acquired primary hyperthyroidism 7B.2a Due to disorder classified elsewhere: Thyroid adenoma (7D.1) Hyperfunctioning carcinoma (7D.2) Non-autoimmune thyroiditis (7E.4) Steinert syndrome (14B.35) 7B.2b Graves disease, hashitoxicosis (Hashimoto s toxicosis) 28 % E05.0 7B.2c Exogenous Thyroid Disorders 45
3 ESPE Code Diagnosis OMIM ICD10 7B.2c.1 Excessive intake of thyroid hormones 29 E05.4 7B.2c.2 Iodine induced ( Jod-Basedow ) E05.4 7B.2y Other specified disorder, e.g. choriocarcinoma, hydatidiform E05.9 mole 7B.2z Idiopathic E05.9 7C GOITRE 7C.0 Due to disorder classified elsewhere Supplementary code only If hypothyroid use code from 7A If hyperthyroid use code from 7B 7C.1 Euthyroid goitre E04 7C.1a Disorders classified elsewhere: Non-autoimmune thyroiditis (7E.4) 7C.1b Dyshormonogenetic E07.1 7C.1b.1 Iodine transport defect 30 # C.1b.2 Organification defects due to an abnormality in the TPO enzyme or in the H 2 O 2 generating system (includes Pendred syndrome) 31 # # # C.1b.3 Defective thyroglobulin synthesis or transport C.1b.4 Abnormal iodotyrosine deiodinase (dehalogenase) activity 33 % C.1c TSH-receptor defects/tsh unresponsiveness # E07.9 # C.1d Iodine deficiency 34 E01, E02 7C.1e Autoimmune/Hashimoto s thyroiditis with normal thyroid % E06.3 function 35 7C.1f Drug-induced/goitrogen exposure E04.8 7C.1g Nodular goitre due to cysts or haemorrhage 36 7C.1y Other specified disorder E04.8 7C.1z Idiopathic (juvenile goitre, adolescent goitre, simple goitre) 37 E04.9 7D T H Y R O I D T U M O U R S 7D.1 Adenomas 38 D34 7D.2 Carcinomas C73, D44 7D.2a Papillary 39 # D.2b Follicular 40 46
4 ESPE Code Diagnosis OMIM ICD10 7D.2c Medullary (C cell carcinoma) 41 7D.2c.1 Sporadic 7D.2c.2 Part of MEN 2A [primary 14C.5b] # D44.8 M8360/1 7D.2c.3 MEN 2B [primary 14C.5c] # D44.8 M8360/1 7D.2c.4 Other familial forms (RET, NTRK1) # D.2d Undifferentiated/anaplastic 7D.2y Other specified carcinoma 7D.2z Other carcinoma, unspecified 7D.8 Other specified tumour E.g. lymphoma, sarcoma D44 C73 7D.9 Other tumour, unspecified D44.0, C73 D34 7E OTHER THYROID DISORDERS 7E.1 Sick-euthyroid syndrome Excluded: Thyroid dysfunction in prematurity (7A.2d) E07.8 7E.2 Disorders of thyroid hormone transport 42 E07.8 7E.2a TBG deficiency E.2b TBG excess 7E.2c Transthyretin (TTR) variants E.2d Familial dysalbuminaemic hyperthyroidism E.3 Thyroid hormone resistance syndromes 43 E07.9 7E.3a Generalised thyroid hormone resistance (GTHR) # E.3b Pituitary resistance to thyroid hormone (PitRTH) # E.3c Peripheral resistance to thyroid hormone (PRTH) # E.4 Non-autoimmune thyroiditis 7E.4a Non-autoimmune thyroiditis due to viral or bacterial agents E06.0 7E.4b Acute suppurative thyroiditis 44 E06.0 7E.4c Subacute thyroiditis E06.1 7E.5 Other thyroid disorders, unspecified Thyroid Disorders 47
5 1 Hypothyroidism Phenotype: Decreased activity, dry skin and hair, excessive weight gain secondary to fluid retention, growth failure, retarded bone age. TSH (+ in primary; /N in secondary/tertiary hypothyroidism), FT4 ( ), FT3 ( ). 2 Congenital (primary) hypothyroidism (CH) Phenotype: Delayed skeletal maturation, enlarged fontanels, constipation, enlarged tongue, lethargy, developmental delay. Thyroid gland either absent, hypoplastic, ectopic, normally-sized or enlarged. In all forms of primary hypothyroidism: low thyroid hormones, elevated TSH. Comments: Heterogenous pathogenesis. 80% due to developmental defects. Neonatal screening enables early diagnosis and treatment. 3 Developmental defects/thyroid dysgenesis Phenotype: Different forms: athyrosis, ectopy, hypoplasia. Diagnosis by thyroid imaging (ultrasound, scintigraphy). 4 Athyrosis/agenesis Phenotype: Most pronounced form of hypothyroidism. Remnants of fibrotic tissue might be detectable. 5 Hypoplasia/hypogenesis Phenotype: Similar as in athyrosis. Remnants of normal tissue can be visualised, but of smaller size than normal. 6 Ectopy Phenotype: Hypothyroidism usually milder than in athyrosis. Normal tissue can be visualised in an abnormal location. 7 Inherited defects of thyroid hormone biosynthesis/thyroid dyshormonogenesis Phenotype: Symptoms and signs of hypothyroidism. Goitre is rare in the neonate, but frequent in older children. 8 Iodine transport defect Phenotype: Inability of the thyroid to maintain a concentration difference of readily exchangeable iodine between the plasma and the thyroid gland. The defect is also found in the salivary gland and gastric mucosa. It is presumed to arise either because of a deficient supply of energy for the transport system or because of abnormality of a carrier or receptor substance. Failure to concentrate radioiodide by the salivary gland (saliva/plasma (123) I ratio was 1.6, in contrast to the normal ratio of more than 20) and the clinical and biologic response to potassium iodide treatment. Comment: The defect in iodide transport is produced by mutations in the sodium-iodide symporter gene (SLC5A5). 9 Organification defect Phenotype: Normal or enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also rapid discharge after perchlorate administration (perchlorate discharge test). 48
6 Comment: Defect of iodine organification (thyroidperoxidase and H 2 O 2 generation defects have been identified). 10 Defective thyroglobulin synthesis or transport Phenotype: Normal or enlarged gland in ultrasound, rapid uptake of radioactive iodine, normal discharge after perchlorate administration (perchlorate discharge test). Tg ( /N/+) (immunoreactivity might be normal). Comment: Defect of the thyroglobulin molecule, which results in an ineffective thyroid hormone production. 11 Abnormal iodotyrosine deiodinase (dehalogenase) activity Phenotype: Normal or enlarged gland in ultrasound, symptoms of CH usually milder than in athyrosis. MIT and DIT elevated in serum and urine. Comment: Defect of the deiodinase which leads to failure of deiodination of iodotyrosine and loss of iodine in the form of MIT and DIT in the urine, frequent development of goitre. 12 TSH-receptor defects/tsh unresponsiveness Phenotype: Normal or hypoplastic thyroid, symptoms of CH usually varying from severe to mild. Tg (N/ ). Comment: Defect of the TSH receptor may be associated with euthyroid hyperthyrotropinaemia or hypothyroidism. 13 Iodine deficiency Synonym: Endemic cretinism. Phenotype: Enlarged, normal or hypoplastic thyroids, symptoms of CH varying from severe to mild. Tg (+), urinary iodine excretion ( ). Comments: Congenital hypothyroidism due to iodine deficiency is common in developing countries. It is preventable by iodine prophylaxis. In some industrialised countries with lesser degrees of iodine deficiency, the incidence of congenital hypothyroidism and hyperthyrotropinaemia is increased as well. 14 Maternal anti-thyroid drug therapy Phenotype: Normal or enlarged thyroid, mild symptoms of CH. Comments: Transplacental passage of anti-thyroid drugs may result in the inhibition of the foetal thyroid function. Condition is transient and disappears with elimination of the anti-thyroid drug from the infant s circulation. 15 Iodine excess Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, however, long-term sequelae are possible. Tg (+), extremely elevated urinary iodine excretion. Comments: Administration of large amounts of iodide, e.g. disinfectants or contrast media to the mother or infant leads to transient suppression of thyroid function (Wolff-Chaikoff effect). Transient hypothyroidism due to iodine excess is frequent in newborns and premature infants in intensive care. Thyroid Disorders 49
7 16 Maternal thyroid autoantibodies Phenotype: Normal or hypoplastic thyroid, symptoms of CH varying from severe to mild. Anti-thyroid antibodies detectable. Comments: Transplacental passage of thyroid autoantibodies (thyroid peroxidase (TPO), TSH receptor, cytotoxic) may disturb thyroid function and development of the foetal thyroid gland. Usually transient condition, in some cases with cytotoxic and thyroid blocking IgG it is permanent. 17 Autoimmune thyroiditis/hashimoto s thyroiditis with decreased thyroid function Phenotype: Thyroid enlarged or normally sized, abnormal echo pattern in ultrasound investigation, mild to severe symptoms of hypothyroidism, short stature. Histology: inflammatory signs, lymphocytic infiltration. Comments: Hypothyroidism due to an inflammation and destruction of thyroid caused by anti-thyroid autoantibodies or viral/bacterial agents. Incidence variable, more frequent in iodine replete areas. 18 Iodine deficiency Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, short stature is the most prominent feature in infants and children. Tg (+), low urinary iodine excretion. Comment: Hypothyroidism due to iodine deficiency caused by inadequate nutritional supply or substances which inhibit iodine uptake, e.g. soy, cassava. 19 Iatrogenic Phenotype: Absent or diminished thyroid tissue, symptoms of hypothyroidism. Comment: Hypothyroidism following the surgical or radiotherapy treatment of hyperthyroidism, cancer or nodular goitre. 20 Iodine excess Phenotype: Enlarged or normal thyroid, symptoms of CH usually mild. Tg (+), extremely elevated urinary iodine excretion. Comment: Administration of large amounts of iodide, e.g. disinfectants or contrast media, infrequently leads to transient suppression of thyroid function in an older child (Wolff-Chaikoff effect). 21 Drug-induced Phenotype: Thyroid enlarged or normally sized, mild to severe symptoms of hypothyroidism, short stature. Comment: Hypothyroidism due to administration of drugs which block thyroid function (perchlorate, carbimazole, methimazole) or iodine uptake (perchlorate, amiodarone) or cause autoimmune inflammation (interferon). 22 Systemic diseases Phenotype: Hypothyroidism, storage of iron, cystin, etc., in the thyroid, usually small glands. Comment: Hypothyroidism as a symptom of systemic disease (e.g. cystinosis, -thalassemia), usually caused by storage of non-thyroidal material or inflammation in the thyroid. 50
8 23 Hyperthyroidism (thyrotoxicosis) Phenotype: Rapid growth associated with restlessness, tremor, heat intolerance, diarrhea, polydipsia and poor concentration. T4 (+), FT4 (+), T3 (+), TSH ( ). TSH suppressed despite TRH stimulation. 24 Congenital hyperthyroidism (neonatal thyrotoxicosis) Phenotype: Manifestations of hyperthyroidism before birth, and in neonatal period. 25 Neonatal thyrotoxicosis due to maternal autoimmune thyroid disease Synonym: Neonatal Graves disease. Phenotype: In utero tachycardia can occur. From birth (or a few days later): thyroid enlarged or normally sized, abnormal echo pattern in ultrasound investigation, mild to severe symptoms of hyperthyroidism, failure to thrive, tachycardia, exophthalmos, restlessness. T4 (+), T3 (+), TSH ( ), measurable stimulating auto-antibodies. Mother has circulating thyroid-stimulating immunoglobulins (TSI). Comments: Hyperthyroidism due to the transplacental passage of thyroid autoantibodies which stimulate the thyroid gland, usually TSH receptor antibodies (TRAb) (TSI). Pregnant women with a history of thyroid disease should be screened for TSI in early pregnancy. In case of positive TSI, foetal heart rate has to be checked regularly. Increased familial occurrence. More frequent in iodinereplete areas. 26 Activating TSH-receptor mutation Phenotype: Thyroid normally sized, rarely enlarged at birth, normal echo pattern in ultrasound investigation, severe symptoms of hyperthyroidism, failure to thrive, tachycardia, relatively resistant to anti-thyroid drug treatment. T4 (+), T3 (+), TSH ( ), no measurable auto-antibodies. Comment: Hyperthyroidism due to constitutively activating mutations of the TSH receptor. 27 G-protein mutations Phenotype: Thyroid normally sized, rarely enlarged, normal echo pattern in ultrasound investigation, severe symptoms of hyperthyroidism, failure to thrive, tachycardia, relatively resistant to antithyroid drug treatment. T4 (+), T3 (+), TSH ( ), no measurable auto-antibodies. Comment: Hyperthyroidism due to constitutively activating mutations of the G-protein signalling pathway, sometimes combined with dysfunction of other endocrine cells, e.g. precocious pseudopuberty, hypo- or hyperparathyroidism (McCune-Albright). 28 Graves disease Synonym: Hashitoxicosis. Phenotype: Thyroid enlarged, abnormal echo pattern in ultrasound investigation, mild to severe symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure, exophthalmos, most severe symptoms evident in thyroid storm. T4 (+), T3 (+), TSH ( ), measurable stimulating auto-antibodies (anti-tsh receptor (TRab) and anti-tpo, and anti-thyroglobulin (Tg) autoantibodies). Comment: Increased familial occurrence. 29 Excessive intake of thyroid hormones Phenotype: Thyroid not enlarged, severe symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure, nausea. T4 (+), T3 (+), TSH ( ). Thyroid Disorders 51
9 Comments: Hyperthyroidism due to large doses of exogenous thyroid hormones. Doses of mg to g of L-thyroxine are needed to produce symptoms, while T3 is more toxic with symptoms already in μg amounts. 30 Iodine transport defect Phenotype: Goitre, enlarged gland in ultrasound, but not visualised in scintigraphy. Tissue can be visualized by decreased iodine content of saliva. T4 (N), TSH (N/+). Comment: Defect of iodine transport into the thyroid and salivary glands. 31 Organification defect Phenotype: Goitre, enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also rapid discharge after perchlorate administration (perchlorate discharge test). T4 (N/ ), T3 (N), TSH (N/+). Comment: Defect of iodine organification (thyroid peroxidase and H 2 O 2 generation defects have been identified). 32 Defective thyroglobulin synthesis or transport Phenotype: Goitre, enlarged gland in ultrasound, rapid uptake of radioactive iodine, normal discharge after perchlorate administration (perchlorate discharge test). T4 (N), TSH (N), Tg ( /N/+) (immunoreactivity might be normal). Comment: Defect of the thyroglobulin molecule, which results in an ineffective thyroid hormone production. 33 Abnormal iodotyrosine deiodinase (dehalogenase) activity Phenotype: Goitre, enlarged gland in ultrasound. T4 (N), TSH (N), MIT and DIT elevated in serum and urine. Comments: Defect of the deiodinase which leads to failure of deiodination of iodotyrosine and loss of iodine in the form of MIT and DIT in the urine, frequent development of goitre. 34 Iodine deficiency Phenotype: Enlarged thyroid. Increased radioactive iodine uptake. There can be a cold nodule. T4 (N), TSH (N), Tg (+), urinary iodine excretion ( ). Comments: Congenital cases: goitre due to iodine deficiency caused by inadequate nutritional supply or substances which inhibit iodine uptake, e.g. soy, cassava. Acquired cases: goitre development due to iodine deficiency is common in many developing countries but also in some industrialised countries with lesser degrees of iodine deficiency. Possible influence of IGF-1, the incidence of juvenile goitre ranges from 0 to 60% in correlation to iodine supply. Can be associated with nodular goitre. 35 Autoimmune/Hashimoto s thyroiditis with normal thyroid function Phenotype: Thyroid enlarged, abnormal echo pattern in ultrasound investigation. Auto-antibodies (anti-tpo, anti-tg, rarely anti-tsh receptor) present. T4 (N) and TSH (N) found in euthyroid cases. Comments: In euthyroid cases the compensatory power of the thyroid is sufficient for normal thyroid hormone production, albeit with an increased gland volume. Increased familial occurrence. 52
10 36 Nodular goitre due to cysts or haemorrhage Phenotype: Goitre, cystic appearance in ultrasound, cold nodule in scintigraphy. T4 (N), TSH (N), no antibodies. Comments: Nodular goitre, nodules represent cysts or haemorrhages. More prevalent in iodine deficient areas. 37 Idiopathic (juvenile goitre, adolescent goitre, simple goitre) Phenotype: Thyroid enlarged. In nodular goitre single or multiple nodules in ultrasound, usually representing cold, very rarely warm or hot nodules in scintigraphy. T4 (N), TSH (N). Comment: Goitre due to multiple nodule formation, probably due to somatic mutations in genes for thyroid specific proteins. 38 Adenomas Phenotype: Thyroid not enlarged, thyroid nodule demonstrable in ultrasound. In cases with hyperthyroidism a hot nodule is found in scintigraphy, and there are mild to severe symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure. Thyroid function can also be normal. Histology: single or multiple nodules without inflammatory signs or lymphocytic infiltration. Comment: Hyperthyroidism due to a hyperfunctioning thyroid nodule carrying a somatic mutation of the TSH receptor gene or G-proteins causing constitutive activation of the thyroid cells. 39 Papillary carcinoma Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as warm nodules in scintigraphy, frequently early lymph node metastases, bilateral occurrence, favourable prognosis. T4 (N), TSH (N). Comments: Most common thyroid tumour in children, relatively differentiated due to rearrangements of ret-proto-oncogenes. More frequent after neck irradiation. 40 Follicular carcinoma Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as warm nodules in scintigraphy, infrequently lymph node metastases, bilateral occurrence, vascular invasion common. T4 (N), TSH (N). Comment: Rare, hard to distinguish from follicular adenoma. More frequent after neck irradiation. 41 Medullary (C cell carcinoma) Phenotype: Single or multiple nodules in ultrasound, usually representing as cold nodules in scintigraphy, early metastasis in lungs and lymph nodes. T4 (N), TSH (N). Elevated calcitonin (after pentagastrin). Comments: In 75% sporadic. Rare tumour caused by ret-proto-oncogene mutations, frequently found in MEN IIa and b, which is hard to distinguish from follicular adenoma. In families with MEN or MTC, children should be screened for mutations of the MEN genes. Calcitonin frequently only increased after pentagastrin stimulation. Thyroid Disorders 53
11 42 Disorders of thyroid hormone transport Phenotype: Normal thyroid, euthyroidism. T4 ( ), FT4 (N), TSH (N). Comment: Usually euthyroid conditions with low measurements of total thyroid hormones but normal free thyroid hormones due to defects of thyroid hormone binding proteins (TBG, albumin). 43 Thyroid hormone resistance syndromes Phenotype: Ranging from overt hypothyroidism with deafness and mental retardation to mild hypothyroidism combined with hyperthyroid symptoms, e.g. tachycardia. Normal thyroid. T4 (+), TSH (+). Comment: Hypothyroidism due to defects of the nuclear T3 receptor with a variable clinical picture ranging from overt hypothyroidism to a mixed clinical picture of hypothyroidism and hyperthyroidism due to different regulation of T3 receptors in different tissues. 44 Acute suppurative thyroiditis Phenotype: Goitre, pain, fever, dysphagia (acute) or weakness, malaise, tenderness of the thyroid (sub-acute), elevated ESR and CRP. T4 (N/ /+), TSH (N/+/ ), no antibodies. 54
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