Congenital Adrenal Hyperplasia ( CAH ) and Congenital Hypothyroidism (CH)

1. Congenital Adrenal Hyperplasia (CAH) andCongenital Hypothyroidism (CH) the importance of newborn screening Balázs Gellén MD. Ph.D. Dept. of Pediatrics University of Szeged

2. Congenital adrenal hyperplasia (CAH) Refers to autosomal recessive diseases resulting from mutations of genes for enzymes mediating the steroidogenesis from cholesterol by the adrenal glands

3. Associated conditions The symptoms of CAH vary depending upon the form of CAH and the gender of the patient. Symptoms can include: • Due to inadequate mineralocorticoids: - vomiting due to salt-vasting leading to dehydration and death • Due to excess mineralocorticoids: - hypertension (11 β-OH deficiency) • Due to excess androgens: - ambiguous genitalia in some females, such that it can be initially difficult to determine sex - early pubic hair and rapid growth in childhood - precocious puberty or absent or delayed puberty - virilization (enlarged clitoris and shallow vagina), and/or menstrual irregularity in adolescence - infertility due to anovulation

4. Classification • Cortisol production begins in the second month of fetal life. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the androgen-producing cells of the adrenal cortex. • Synthesis of cortisol shares steps with synthesis of mineralocorticoids, androgens, and estrogens. • The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH.

6. 11β-hydroxylase

8. 21-hydroxylase deficiency • The defective enzyme is P450c21 (cytochrome P450 oxidase ), commonly referred to as 21-hydroxylase (21-OH), encoded by the CYP21 gene. • CAH due to 21-OH deficiency accounts for about 95% of diagnosed cases of CAH. • The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition. • The incidence of salt wasting CAH is 1in 15,000 children !!!

9. 21-hydroxylase CAH is inherited in an autosomal recessive fashion CYP21 is paired with a nonfunctional pseudogene CYP21P

10. Penetrance Variabilityand recombination of abnormal alleles of CYP21 and homologous region of CYP21P geneis introduced by the degree of enzyme inefficiency. • severe degrees produce changes in the fetus and problems in prenatal or perinatal life • milder degrees are usually associated with excessive or deficient sex hormone effects in childhood or adolescence • the mildest form of CAH interferes with ovulation and fertility in adults

12. Newborn screening 1. Conditions justifying newborn screening for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire and severe consequence if not diagnosed early, (3) an effective treatment if diagnosed, (4) a frequency in the population high enough to justify the expense.

13. Newborn screening 2. In the last decade more countries are adopting newborn screening for salt-wasting CAH due to 21-OH deficiency, which can leads to death in the first month of life if not recognized.

14. Newborn screening 3. • Currently, in over 40 countries, every child born is screened for CAH at birth. This test will detect elevated levels of 17-hydroxy-progesterone (17-OHP). • Detecting high levels of 17-OHP enables early detection of CAH. • Newborns detected early enough can be placed on medication and live a relatively normal life.

15. Newborn screening 4. • The salt-wasting form of CAH is potentially fatal within a month if untreated. • Steroid replacement is a simple, effective treatment. • However, while the 17OHP level is easy to measure and sensitive (rarely missing real cases!!), the test has a poorer specificity. • It’s a higher rate of false positives than the screening tests for many other congenital metabolic diseases.

16. Newborn screening 5. • When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. • Since most infants with salt-wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate.

17. The main future directions and discussions in development of CAH treatment: • debate over the value of genital reconstructive surgery and changing standards • debate over sex assignment of severely virilized XX infants • new treatments to improve height outcomes • newborn screening programs to detect CAH at birth • increasing attempts to treat CAH before birth

18. Basic guidelines of treatment of 21OHD: • supplying glucocorticoid to reduce hyperplasia and overproduction of androgens • providing replacement mineralocorticoid and extra salt if the person is deficient • additional treatments to optimize growth by delaying puberty or delaying bone maturation • genital reconstructive surgery if necessary • psychotherapy

21. CAH Passport Emergency Medical Information Card For the emergency room physician: In the situation of adrenal crisis the patient will need 1.) Immediate IV normal saline with 5 % glucose 20 ml/kg in one hour followed by continuous and appropriate IV fluid replacement in children, a liter of normal saline with 5 % glucose in one- two hours in adults followed by continuous and appropriate IV fluid replacement and 2.) Solu-Cortef, or Hydro-Adreson F Aquosum IV bolus injection: younger than 3 years: 25 mg, 3-10 years: 50 mg, in adolescents and adults: 100 mg. Thereafter during the time of acute crisis, administer for infantsSolu-Cortef 25-30 mg/day by IV drip or 4 divided doseses IM or IV, for young children50-60 mg/day by continuous IV drip or 4 divided doseses IM or IV, and for adolescents and adults100 mg/day by continuous IV drip or 4 divided doseses IM or IV. • Name: • Date of Birth: • Address: • Parental phone number: • Doctor’s phone number: • Dg.:Congenital adrenal hyperplasia (21OHD) Salt-wasting form/Simple virilising form Hospital responsible for the care of patient CAH is a special form of adrenal insufficiency. The patient needs continuous STEROID replacement therapy. Maintenance dose: Increase to two to three times regular dosage during periods of intercurrent illness or other periods of stress. IN EMERGENCY: (severe stress or trauma, adrenal crisis) GIVE Hydrocortisone* intravenously/intramuscularly 3-6 mg/kg or 50-100 mg/m2as a first aid before transporting the patient to a hospital. * Inj. Hydro-Adreson F Aquosum, Inj. Solu-Cortef, Solu -Medrol

22. „thyreos = shield” (Thomas Wharton 1656 London) • thyroid hormons: thyroxin ,trijodthyronin - iodine content dipeptid hormons • Key factor in: - growing - metabolism - development of cardiovascular system - development of central nervous system

23. Thyroid stimulating hormone (TSH) • TSH is a noncovalently linked glycoprotein heterodimer and is part of a family of pituitary hormones containing a common alpha subunit and a unique beta subunit that confers specificity.

24. TSHR • The thyroid-stimulatinghormonereceptor is a receptor (and associated protein) that responds to thyroid-stimulating hormone, and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily. • It is primarily found on the surface of the thyroid epithelial cells.

25. Paired box gene 8 - PAX8 - a member of the paired box (PAX) family • This gene encoded a transcription factor protein. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. • Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas.

26. Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. • Approximately 1 in 3000 newborn infants has a severe deficiency of thyroid function, while even more have mild or partial degrees. • If untreated for several months after birth, severe CH can lead to growth failure and permanent mental retardation. • Treatment consists of a daily dose of thyroid hormone (thyroxine) by mouth. • Because the treatment is simple, effective, and inexpensive, nearly all of the developed world practices newborn screening to detect and treat CH in the first 7-14 days of life.

27. ETIOLOGY of CH (1.) • In the past the most common cause WAS iodine deficiency, but in most of the developed world areas of adequate environmental iodine and iodine supply reduce this problem. • Defect of development of the thyroid gland itself, resulting in an absent (agenesia) or underdeveloped (hypoplastic) gland. A hypoplastic gland may develop higher in the neck or even in the back of the tongue or other region (ectopic). • result from genetic defects, and some are "sporadic," with no identifiable cause. • CH detected by screening may be transient • most common cause of this is the presence of maternal antibodies which temporarily impair or inhibits thyroid function for some week.

28. ETIOLOGY of CH (2.) • 85% thyreoid gland dysgenesis organification def. agenesia, hypoplasia, ectopia • 10% dyshormongenesis - defects of thyroxine or triiodothyronine synthesis within a structurally normal gland - nongoitrous CH TRH,TSH ,TSHR def.,TSH resistance, iodine trapping and transport def., thyroglobulin def., deiodinase, peroxydase def., G-protein def. • 2% transcription factor gene mutation TTF1, TTF2, PAX8 • 3% others – maternal radio-iodine therapy during pregnancy etc.

29. DIAGNOSTIC EVALUATION - Newborn screening 1. Nearly all cases of congenital hypothyroidism can be detected by the newborn screening program. - These are based on measurement of TSH (and/or in some countries free thyroxine - fT4) on the second or third day of life.

30. DIAGNOSTICEVALUATION - Newborn screening 2. Ifthe TSH is high (orthe fT4 low), thescreening labor must callsinfant'sdoctor (or GP), parents and regionalpediatricendocrinologist and the baby must be referredto a pediatricendocrine centertoconfirmthe diagnosis and initiatetreatment. Often a technetium (Tc-99m pertechnetate) thyroid scan is performedatdiagnosistodetect a structurally abnormalgland (becauseit has no therapeutic consequences, usuallywerecommenditlateragein Hungary).

31. Newborn screening 3. • In Hungary: - Incidency of CH: 1:3000 - Screening program from 1984: Guthrie-test (+ PKU, galactosaemia, biotinidase def. - MTS) - measurement of TSH must be on the 2nd or 3rd day of life – DRIED BLOOD SPOT If TSH > 30 μU/ml the infant must be transported to the regional pediatric endocrinology and screening center to confirm the diagnosis and initiate treatment. If TSH = 20-29 μU/ml– test must be repeated immidiately

32. Symptoms 1. • Infants born with CH may show no effects, or may display mild effects that often go unrecognized as a problem (!) • If fetal deficiency was severe because of complete absence of the gland, physical features may include more characteristic signs

33. Classic signs: excessive sleeping, reduced interest in nursing, bad appetite, poor muscle tone, low or hoarse cry, infrequent bowel movements, constipation, exaggerated jaundice, low bodytemperature, dry skin, larger anterior fontanel, persistence of a posterior fontanel, umbilical hernia, large tongue (macroglossia), lethargia, wide nasal sella, oedema, bradycardia and sometimes - goiter .

34. Symptoms2. • In the era before newborn screening, less than half of cases of severe hypothyroidism were recognized in the first month of life (!) These infants would grow poorly and be delayed in their development. • By several years of age, they would display the recognizable facial and body features of cretinismwith severe mental and physical retardation, with an IQ below 80 in the majority.

35. Treatment 1. • The goal of newborn screening programs is to detect and start treatment within the first 1–2 weeks of life. • Treatment consists of a daily dose of thyroxine, available as a small tablet. The generic name is levothyroxine, and several brands are available. • The tablet is crushed and given to the infant with a small amount of water or milk.

36. Treatmnet 2. • The most commonly recommended dose about 12-15 μg/kg daily, typically 50 (or 37,5) μg. • Within a few weeks, the freeT4 and TSH levels are rechecked to confirm that they are being normalized by treatment. • As the child grows up, these levels are checked regularly to maintain the right dose.

37. Treatment guideline: Dosage: 12-15 μg/kg/day LT4 ≈ 50μg= 1tbl/day LT4 (Letrox, Euthyrox, L-Thyroxin) to maintain the right dose of LT4 based on clinical signs and regular checked lab results of serumTSH, freeT4 (and dried blood spotTSH) Timepoint of regular checking: 1-3 months of age - monthly 3-12 months of age – 2-3 monthly 1-2 years of age – 4 monthly 2-3 years of age – 6 monthly From 3 years of age - 6-12 monthly

38. Prognosis • Most children born with CH and correctly treated with thyroxine grow and develop normally in all respects, develop with normal intelligence. • In some cases, the CH patients as a population academic performance tends to be below that of siblings and may occur mild learning problems (due to bad compliance?, due to intrauterin hypothyreoid condition?) Congenital hypothyroidism is the most common preventable cause of mental retardation. Few treatments in the practice of medicine provide as large a benefit for as small an effort.

39. Other benefits of TSH-screening The dried blood spot test forTSH is a capabel method to screen and check not only CH but all hypothyreoid patients. The GP, parents, welfare nurse can take easily the sample, and send it by post to the Endocrine Center (between two outpatient clinic visits) • to follow the efficacy of treatment, • to maintain the right dose of LT4, • to check and improve compliance.

42. Hypothyreosis ● ● ● ● ● ● ● ● ● ● ● LT4 rhGH ●