Common Thyroid Disorders in Children . Common Thyroid Disorders in Children Dr Sarar Mohamed FRCPCH (UK), MRCP (UK), CCST (Ire), CPT (Ire), DCH (Ire), MD Consultant Paediatric Endocrinologist & Metabolist Assistant Professor of Pediatrics King Saud University

Endocrine Glands

Agenda Thyroid Anatomy and physiology Thyroid Function Test . Thyroid Anatomy and physiology Thyroid Function Test Congenital Hypothyroidism Newborn screening for congenital hypothyroidism Acquired hypothyroidism Hyperthyroidism Causes of goitre

Newborn Screening

THYROID GLAND Location: Located close to thyroid cartilage. Has two lateral lobes connected by thyroid isthmus medially. Development: first endocrine gland to appear during development. Develops from endodermal floor of early pharynx

THYROID GLAND Functions: Innervation: Vagus Nerve (X) Arterial Supply: superior thyroid artery (branch of external carotid artery). Functions: THYROXIN – regulate rate of metabolism CALCITONIN – decreases levels of calcium and phosphate in the blood (partially antagonistic to parathyroid hormone).

Production of Thyroid Hormones NIS (Na+/I- Sympoter) TPO

t1/2 = 5-7d t1/2 = < 24 hrs

Normal Daily Thyroid Secretion Rate: T4 = 100 ug/day T3 = 6 ug/day ( ratio T4:T3 = 14:1 ) T4 Protein binding + 0.03% free T4 85% (peripheral conversion) T3 Protein binding + 0.3% free T3 15% (10-20x less than T4)

T4 T3 Potency 1 10 Protein Bound 10-20 Half-Life 5-7d < 24h Secreted by thyroid 100 ug/d 6 ug/d

Thyroid Function: blood tests TSH 0.4 –5.0 mU/L Free T4 (thyroxine) 9.1 – 23.8 pM Free T3 (triiodothyronine) 2.23-5.3 pM

Effects of thyroid hormones Fetal brain & skeletal maturation Increase in basal metabolic rate Inotropic & chronotropic effects on heart Stimulates gut motility Increase bone turnover Increase in serum glucose, decrease in serum cholesterol Play role in thermal regulation

Dysfunction Thyroid Gland 1. Too little thyroxin – hypothyroidism a. short stature (aquiered), developmental delay (congenital) 2. Too much thyroxin – hyperthyroidism a. Agitation, irritability, & weight loss

Hypothyroidism Decreased thyroid hormone levels Low T4 Possibly Low T3 too. Raised TSH (unless pituitary problem!)

Causes of hypothyroidism . Causes of hypothyroidism Congenital Autoimmune (Hashimoto) Iodine deficiency Subacute thyroiditis Drugs (amiodarone) Irradiation Thyroid surgery Central hypothyroidism (radiotherapy, surgery, tumor)

Clinical features of Acquired hypothyroidism . Weight gain Goitre Short sature Fatigue Constipation Dry skin Cold Intolerance Hoarseness Sinus Bradycardia

Hypothyroidism with short stature

. Diagnosis High TSH, low T4 Thyroid antibodies

Hashimoto’s Disease Most common cause of hypothyroidism Autoimmune lymphocytic thyroiditis Antithyroid antibodies: Thyroglobulin Ab Microsomal Ab TSH-R Ab (block) Females > Males Runs in Families!

Subacute (de Quervain’s) Thyroiditis Preceding viral infection Infiltration of the gland with granulomas Painful goitre Hyperthyroid phase  Hypothyroid phase

Treatment of Hypothyroidism Replacement thyroid hormone medication: Thyroxine

Congenital Hypothyroidism: Causes . Congenital Hypothyroidism: Causes Agenesis or dysgenesis of thyroid gland Dyshormonogenesis Ectopic gland Maternal hypothyroidism

Mother supplies T4 to fetus via placenta Newborn Screening Facts Normal Newborn Mother supplies T4 to fetus via placenta Immature Hypothalamic Pituitary Thyroid Axis Mother Fetus T4 Mid-Gestation T4 Mature Hypothalamic Pituitary Thyroid Axis Euthyroid Mother Pregnancy

Clinical Features of Congenital Hypothyroidism Newborn Screening Clinical Features of Congenital Hypothyroidism Finding % Lethargy 96% Constipation 92% Feeding problems 83% Respiratory problems 76% Dry skin Thick tongue 67% Hoarse cry Umbilical hernia Prolonged jaundice 12% Goiter 8%

Newborn Screening

X suspect Confirm Rx & FU Congenital Hypothyroidism Clinical Newborn Screening Congenital Hypothyroidism X suspect Clinical Biochemical (screening) Confirm Lab ( TSH & FT4 ) Optional T scan B age Rx & FU Thyroxine Growth & D TSH & FT4

Management Primary Congenital Hypothyroidism Thyroxine Dose Form Goals Newborn Screening Management Primary Congenital Hypothyroidism High TSH & Low T4 Thyroxine Dose Form Goals 10 -15 ug/kg/day 12 -17 ug/kg/day 37.5 – 50 ug/day Higher dose in Severe cases T4< 5ug/dl Tablets 25-50-75 ug Crush it, add to 5-10 cc water Or milk Normal T4 In 2 wks (upper ½ of N) Normal TSH In one month (lower ½ of N)

Screening: search for a disease in a large unselected population PKU Newborn Screening Definitions Screening: search for a disease in a large unselected population PKU Congenital hypothyroidism

Principal of newborn screening Aim is to identify affected infants before development of clinical signs

Success Stories in Pediatric Medicine Newborn Screening Success Stories in Pediatric Medicine Immunization programs Newborn Screening program Oral Rehydration Therapy Pencillin

Newborn Screening Phenylketonuria Guthrie Test 1962, Robert Guthrie

Possible screening tests Newborn Screening Possible screening tests Beta-ketothiolase deficiency (BKT) < 1 in 100,000 Propionic acidemia (PROP) > 1 in 75,000 Adenosylcobalamin synthesis defects Multiple-CoA carboxylase deficiency (MCD) < 1 in 100,000 Carnitine palmityl transferase deficiency type 2 (CPT) Long-chain acyl-CoA dehydrogenase deficiency (LCAD) Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) > 1 in 75,000 Short-chain acyl-CoA dehydrogenase deficiency (SCAD) Short-chain hydroxy Acyl-CoA dehydrogenase deficiency (SCHAD) Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) > 1 in 25,000 Very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD) > 1 in 75,000 Carnitine/acylcarnitine Translocase Deficiency (Translocase) Multiple acyl-CoA dehydrogenase deficiency (MADD) Trifunctional protein deficiency (TFP) < 1 in 100,000 Carnitine uptake defect (CUD) < 1 in 100,000 Congenital toxoplasmosis HIV Cystic fibrosis (CF) > 1 in 5,000 Maternal vitamin B12 deficiency Congenital hypothyroidism (CH) > 1 in 4,000 Biotinidase deficiency (BIOT) > 1 in 75,000 Congenital adrenal hyperplasia (CAH) > 1 in 25,000 Classical galactosemia (GALT) > 1 in 50,000 Glucose-6-phosphate dehydrogenase deficiency (G6PD) Sickle cell anemia (Hb SS) > 1 in 5,000; among African-Americans 1 in 400 Sickle-cell disease (Hb S/C) > 1 in 25,000 Hb S/Beta-Thalassemia (Hb S/Th) > 1 in 50,000 Tyrosinemia I (TYR I) < 1 in 100,000 Tyrosinemia II Argininemia Argininosuccinic aciduria (ASA) < 1 in 100,000 Citrullinemia (CIT) < 1 in 100,000 Phenylketonuria (PKU) > 1 in 25,000 Maple syrup urine disease (MSUD) < 1 in 100,000 Homocystinuria (HCY) < 1 in 100,000 Glutaric acidemia type I (GA I) > 1 in 75,000 Glutaric acidemia type II HHH syndrome (Hyperammonemia, hyperornithinemia, homocitrullinuria syndrome) Hydroxymethylglutaryl lyase deficiency (HMG) < 1 in 100,000 Isovaleric acidemia (IVA) < 1 in 100,000 Isobutyryl-CoA dehydrogenase deficiency 2-Methylbutyryl-CoA dehydrogenase deficiency 3-Methylcrotonyl-CoA carboxylase deficiency > 1 in 75,000 Beta-methyl crotonyl carboxylase deficiency 3-Methylglutaconyl-CoA hydratase deficiency Methylmalonyl-CoA mutase deficiency (MUT) > 1 in 75,000 Methylmalonic aciduria, < 1 in 100,000

Congenital Hypothyroid Newborn Screening Congenital Hypothyroid Screening started 1974 in Quebec & Pittsburgh Objective : Eradication of MR secondary to CH Incidence 1:3000 – 4000 ( more than PKU ) Female : Male is 2 : 1

Congenital Hypothyroidism Newborn Screening Congenital Hypothyroidism One of the most common Treatable causes of MR CH Screening is the most cost effective program Almost all affected NB have no S/S at birth Congenital Anomalies increased by 10%(cardiac) In more than 90% of the cases it is permanent The earlier dx the better IQ

Newborn Screening Criteria Wilson Criteria Incidence >1/100,000 Significant morbidity/mortality Successful treatment Reasonable cost Test: specific/sensitive/acceptable Congenital hypothyroidism 1/3,000 to 1/4,000 Mental retardation Thyroxine $3.00 immunoassay This slide illustrates the diseases in relation to the newborn screening criteria – as we must consider this criteria prior to adding on new disease screening. As you can see here, the combination of these conditions are estimated to affect approximately 1 in 5,000 to 1 in ten thousand livebirths. The conditions can cause severe medical complications or death - FAOD alone are thought to account for 5% of sudden infant death. Treatment in the form of dietary management and avoidance of fasting, is effective at preventing mortality and improving quality of life. The initial cost of performing the analysis by tandem mass spec for these disorders is less than $10.00. Although effective treatments do not exist yet for all of the metabolic disorders identifiable by tandem mass spectrometry,it is thought that some advantage can be achieved for the family and healthcare professionals through early diagnosis. This benefit is clearly seen when even though a child may die in the neonatal period before results are available information is now available for future reproductive use.

Screening Technique Newborn Screening Specimen is a blood spot in a filter paper Obtained by heel brick Or cord blood

Newborn Screening

Newborn Screening

Newborn Screening Good Specimen

Every Newborn is considered Until Proven Otherwise . Congenital Hypothyroidism Objective from screening: Eradication of MR secondary to CH Every Newborn is considered Hypothyroid Until Proven Otherwise

Both Method & Timing of Thyroid Screening Cord TSH&T4 Venous Blood Newborn Screening Method & Timing of Thyroid Screening Primary-TSH Backup-T4 Both TSH&T4 Primary-T4 Backup-TSH Venous Blood Cord Blood Age At Birth Age 2-5 days

Clinical Outcome Pre-screening data: Newborn Screening Mean IQ = 76 Age of Diagnosis % with IQ > 85 3 months 78% 6 months 19% > 7 months 0%

Clinical Outcome Post-screening data: Newborn Screening Children screened & treated by age 25 days Mean IQ = 104

Newborn Screening > screening < screening

Congenital Hypothyroidism Newborn Screening X Congenital Hypothyroidism

Hyperthyroidism Increased thyroid hormone levels High T4 +/- High T3 Low (suppressed) TSH

Causes of hyperthroidism . Causes of hyperthroidism Graves Disease Overtreatment with thyroxine Thyroid adenoma (rare) Transient neonatal thyrotoxicosis

Graves’ Disease Most common cause of hyperthyroidism Goitre, proptosis TSH-R antibody (stimulating) 40-70% relapse after 2 years of treatment

Hyperthyroidism S&S Heat intolerance Hyperactivity, irritability Weight loss (normal to increased appetite) diarrhea Tremor, Palpitations Diaphoresis (sweating) Lid retraction & Lid Lag (thyroid stare) proptosis menstrual irregularity Goitre Tachcardia

Tremor of the hand A Color Atlas of Endocrinology p49

Neonatal hyperthyroidism born to mother with Graves’ disease A Color Atlas of Endocrinology p51

“Exophthalmos”

Grave’s ophthalmopathy

Hyperthyroid Eye Disease

investigations . TSH, free T3&T4 Thyroid antibodies (TSH receptors antibodies) Radionucleotide thyroid scan (incease uptake)

Hyperthyroidism Treatment Beta-blockers Carbimazole PTU (propylthiouracil) Radioactive iodine (in adults) surgery

. Causes of goitre Congenital (maternal antithyroid drugs, maternal hyperthyroidism, dyshormonogenesis) Physiological (puberty) Iodine deficiency Graves disease Hashimoto thyroiditis Tumor

Goiter A swollen thyroid gland

Thank You! Newborn Screening