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UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) UvA-DARE (Digital Academic Repository) Congenital hypothyroidism beyond neonatal T4 screening: progress in diagnostics and treatment Bakker, E. Link to publication Citation for published version (APA): Bakker, E. (2000). Congenital hypothyroidism beyond neonatal T4 screening: progress in diagnostics and treatment. Amsterdam: Bert Bakker. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 28 Jan 2020

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Page 1: UvA-DARE (Digital Academic Repository) Congenital ... · GenerallIntroduction 1.1.2.2.1..Hyporesponsivenesst oTSH. Defectssinth eTSHReceptor. AbnormalitiessintheaSubunitoftheGProtein

UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Congenital hypothyroidism beyond neonatal T4 screening: progress in diagnostics andtreatment

Bakker, E.

Link to publication

Citation for published version (APA):Bakker, E. (2000). Congenital hypothyroidism beyond neonatal T4 screening: progress in diagnostics andtreatment. Amsterdam: Bert Bakker.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 28 Jan 2020

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Chapter r 1 1

Generall Introduction

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Chapterr 1

Preface . .

I.. Thyroi d Physiolog y and Developmen t (Introductio n to Patho-Physiology) . 1.1.. Development of Hypothalamus and Pituitary Gland.

1.2.. Development of the Human Thyroid Gland.

1.3.. Thyrotropin Releasing Hormone (TRH).

1.44 T5H Synthesis and Secretion.

1.5.. Thyroid Hormone Receptor.

1.6.. lodothyronine Deiodinases.

1.7.. Thyroidal Iodine Metabolism.

Iodinee Deficiency Disorders.

1.8.. Thyroid Determinants in Plasma.

1.8.1.. TSH.

1.8.2.. Thyroxine (T4).

1.8.3.. Triiodothyronine (T3).

1.8.4.. Free Thyroxine (FT4).

1.8.5.. Thyroxine Binding Proteins.

1.8.6.. Thyroglobulin (Tg).

1.9.. Thyroid Determinants in Urine.

1.9.1.. Urinary iodine excretion.

1.9.2.. LOMWIOM.

1.10.. Maternal-Fetal Transfer of Thyroid-Hormone.

1.11.. Neonatal CH Screening.

II.. Thyroi d Patholog y (Especiall y the Etiologi c Classificatio n of CH). 1.. Permanent Congenital Hypothyroidism.

1.1.. Central CH (Hypothalamic or Pituitary CH).

1.1.1.. Defects in the TRH Receptor.

1.1.2.. Defects in the Regulation of TSH Synthesis and Secretion.

1.1.3.. Defects in TSH Synthesis.

1.2.. Thyroidal Congenital Hypothyroidism (= Primary CH).

1.2.1.. Thyroid Dysgenesis (Thyroid Developmental - or Embryonic

Developmentt Disorder).

Thyroidd agenesis.

Cryptopicc thyroid remnant.

Dystopicc thyroid remnant.

Eutopicc remnant.

1.11 2.2. Thyroid dyshormonogenesis.

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Generall Introduction

1.1.2.2.1.. Hyporesponsiveness to TSH.

Defectss in the TSH Receptor.

Abnormalitiess in the a-Subunit of the G Protein.

TSHH Hyporesponsiveness Caused by Other Factors.

1.1.2.2.2.. Iodide Transport Defect.

1.1.2.2.3.. Defects in lodination of Thyroglobulin (Organification Defects).

Thyroidd peroxidase defects (TIOD and PIOD).

Pendred'ss Syndrome (PDS).

1.1.2.2.4.. Defects in Thyroglobulin Synthesis.

1.1.2.2.5.. Defects in Recycling of Iodide.

1.2.. Transient CH.

Iodidee excess.

Inhibitingg maternal antithyroid immunoglobulins.

Maternall anti-thyroid medication.

Transientt hypofunction in the premature neonate.

III.. Diagnosi s of CH . 11.1.. Imaging Studies in CH.

11.1.1.. Thyroid Ultrasound Studies.

11.1.2.. Thyroidal Radioiodide Uptake (123l uptake).

Perchloratee Discharge Test.

IV.. Treatmen t / Thyroxin e Supplementatio n in CH. V.1.. T4 Supplementation.

V.2.. Euthyroidism.

V.. Some Geneti c Aspect s of CH. Generall definitions.

Genomicc imprinting.

Uniparentall Disomy (UPD).

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Chapterr 1

Preface . .

Congenitall Hypothyroidism (CH) is one of the few diseases we screen for during the neonatal

periodd because CH in neonates is difficult to recognize by symptoms and signs, and early

detectionn and treatment is essential. The reason for screening is to prevent damage to the

centrall nervous system arising from thyroid hormone deficiency. While thyroid hormone in

generall exerts a broad range of effects on development, growth, and metabolism, it is

importantt to stress that with respect to CH this substance is particularly important for brain

development.. Shortage of the hormone during prenatal life and the first years after birth

resultss in a spectrum of neuropsychological disorders, depending on the duration and severity

off the deficiency (84,63,94,1 50). Prenatal brain development in CH is largely preserved by a

limitedd but substantial maternal supply of thyroxine (T4) (40). After birth therefore, the

administrationn of T4 must be started as early as possible (46,140) with adequate daily dosages

off T4 (3,79) especially when patients are completely unable to synthesize thyroid hormone.

Thiss thesis is about the diagnostic and therapeutic process in CH.

Thee topic of this thesis covers determinants of thyroid function in urine and plasma (Chapters

22 and 3) related to diagnostics and therapy as well as methods of molecular biology as

appliedd in the field of CH (chapters 4 - 6). Without molecular biology we would only

partiallyy understand what is at the root of the thyroid dysfunction in a number of CH

children.. Within the field of thyroidology (and CH in particular), genetic determinants are

important.. Within the context of this dissertation examples of mutations in different genes

relatedd to CH are given. Clinical (pediatric) endocrinologists need the knowledge of molecular

biology,, as well as the understanding of the applied methods, in order to use these

approachess in daily clinical care as a (pediatric) endocrinologist. Thus, a good cooperation

withh the research staff in the laboratory with detailed knowledge of molecular biology,

biochemistry,, and clinical chemistry amongst others is needed. I was lucky and happy to be

inn such a setting over the last six years. This cooperation is reflected in this thesis.

Thee first part (I) of this general introduction is about the ontogeny of hypothalamus, pituitary,

andd thyroid gland; also about thyroid physiology and some patho-physiology; and finally

aboutt determinants of thyroid function measured in plasma and urine. Part II is about

neonatall thyroid pathology, especially CH. Part III is on the diagnostic process, where the

importancee of finding the right etiology is stressed. Part IV is on treatment of CH (T4

supplementation)) and Part V is an introduction to some relevant genetic aspects of

congenitall thyroid diseases.

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Generall Introduction

I.. Thyroi d physiolog y and development , introductio n too pathophysiology .

Thyroidd hormone exerts a broad range of effects on development, growth, and metabolism.

Thee clinical manifestations of thyroid hormone deficiency and excess are dramatic expressions

off the multiple actions of thyroid hormone. Thyroxine (T4), the primary secretory product

off the thyroid gland, is inactive until it is converted to the active hormone triiodothyronine

(T3),, by iodothyronine deiodinases (IDs). T4 can be considered a prohormone.

Thee actions of thyroid hormone are primarily the result of the interaction of T3 with nuclear

receptorss for T3 (T3-R) that bind to regulatory regions of genes, named Thyroid hormone

Responsivee Elements (TREs), and modify their expression (74,15). These receptors have

beenn cloned (103), and there has been considerable progress in unraveling the various

mechanismss by which thyroid hormone regulates gene expression.

Figur ee 1 : Anatomy of the neck with a clear view of the thyroid gland wrapped around the trachea.

Thee synthesis of thyroid hormone takes place in the thyroid gland, which is located in the

lowerr part of the neck, ventral of the trachea (Figure 1). The functional unit of the thyroid

iss the follicle, formed by a single layer of follicular cells surrounding a lumen (Figure 2). The

lumenn contains thyroglobulin (Tg) that serves as a matrix for the synthesis of thyroid

hormones,, which takes place at the apical border of the follicular cells. Circulating plasma

iodidee is actively transported into the follicular cells and is organified through a series of

enzymaticallyy catalyzed steps to form thyroid hormones (Figure 3). The following proteins

aree important for the synthesis of thyroid hormone: Na'/I symporter (NIS) for trapping the

iodide;; the large glycoprotein thyroglobulin (Tg) as a matrix for thyroid hormone synthesis;

pendrinn that may play a role in the transport of iodide; thyroid peroxidase (TPO) and the

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Chapteii 1

Figur ee 2: Scanning electron micrograph of thyroid gland of a dog with two opened follicles (F). The luminall aspect of individual follicular cells protrudes into the follicular lumen (arrowhead). Interfollicular spacee (I) with connective tissue and capillaries is present (From Braverman LE, Utiger RD, eds. Werner && Ingbar's The Thyroid 1" ed. Philadelphia-New York, with permission from Lippincott Raven, Philadelphia,, PA, USA).

H_,022 generating system [thyroid oxidases (ThOX 1 and 2)] as the most important enzymes

inn thyroid hormone synthesis. These proteins will be discussed in more detail in this

introduction. .

Figur ee 3: Schemati c representatio n of th e biosyntheti c pathwa y of th e thyroi d hormone s T3 andd T4 in th e thyroi d follicula r cell . The basolateral surface of the cell is shown on the left side of the figure,, and the apical surface on the right. Active accumulation of I, mediated by the Na'/I symporter (NIS)) [circle]; Na",K"-ATPase [triangle]; TSH receptor [square]; adenylate cyclase [diamond]; G protein [ellipse];; I efflux toward the colloid [tube]; TPO catalyzed organification of I [TPO]; endocytosis of iodinatedd Tg, followed by phagolysosomal hydrolysis of endocytosed iodinated Tg and secretion of bothh thyroid hormones [<-].(from Thyroid Today, with permission from GEM Communications, Norwalk, CT,, USA).

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Generall Introduction

1.1.. Development of Hypothalamus and Pituitary Gland.

Thee pituitary gland is formed by fusion of an invagination of the floor of the third cerebral

ventriclee and Rathke's pouch which is an invagination of the oral ectoderm. Subsequently

theree is differentiation of the five types of cells that produce the different pituitary hormones:

thyrotropes,, somatotropes, lactotropes, gonadotropes, and corticotropes. During fetal

developmentt of the anterior pituitary gland, a number of sequential processes occur that

regulatee cell differentiation and proliferation. Molecular analyses have revealed several

stepss that are required for pituitary cell line specification and have identified specific factors

thatt control these steps. Several homeobox genes have been implicated in the development

off the pituitary gland, including HESX1, PROP1, POU1F1, and PTX( 128,132,133,134,142,184).

Thee POU1 F1 and PROP1 gene encode for pituitary specific transcription factors affecting

thee formation of thyrotropes, somatotropes, and lactotropes (42,68,128). PROP1 in addition,

alsoo plays a direct or indirect role in the ontogeny of pituitary gonadotropes (184). HESX1

encodess for a transcription factor required for the development of the forebrain, eyes, and

otherr anterior structures such as the hypothalamus, the pituitary gland, and olfactory

placodess (as found in mice). Defects in HESX1 in mice cause disorders that are comparable

withh septo-optic dysplasia in humans (33). Hypoplasia of the optic nerves, various types of

forebrainn defects, and pituitary hormone deficiencies, including TSH deficiency characterize

septo-opticc dysplasia. Ptx is a paired homeodomain pituitary transcription factor and the

expressionn of the PTX gene has been demonstrated in human pituitary adenomas. Some

investigatorss hypothesize that Ptx plays a role in the terminal differentiation of the

somatotropess and lactotropes (132).

i.2.. Development of the Human Thyroid Gland.

Thee thyroid gland develops primarily as a ventral bulge of the entoderm at the position of

thee first and second branchial arches in the human embryo (40). Sometimes later in life, a

remnantt of the median 'anlage' is recognizable as the foramen caecum of the tongue

Figur ee 4: Embryology of thyroid andd parathyroid glands and the relationshipp to pnmordia for the u l t imobranchia ll body (From Bravermann LE, Utiger RD, eds. Wernerr & Ingbar's The Thyroid 7" ed.. Philadelphia-New York, with permissionn from Lippincott Raven, Philadelphia,, PA, USA).

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Chapterr 1

foramenn caecum

thyroglossaa duct

primitivee gut

oesophagus s

4 -- trachea

thyroidd gland

Figur ee 5: Embryology of thyroid gland (sagittall view).

(Figuree 4 & 5). About 17 days after conception, the human primordial thyroid can be

detectedd close to the developing heart and around day 30 of embryological life a hollow,

bilobarr structure is formed. During the next step both lobes fuse with the ultimobranchial

bodiess (lateral 'anlage'), which is developed from the fourth branchial pouches. The calcitonin

secretingg cells (C-cells) of the thyroid originate from these ultimobranchial bodies. At eight

weekss after conception the thyrocytes are organized in tubes and two weeks later

intercellularr follicles are formed and iodine can be bound. This indicates that the thyrocytes

aree able to synthesize the enzyme TPO and the large glycoprotein Tg, and to transport

thesee thyroid-specific proteins into the follicular lumen by exocytosis. The number of follicles

increasess for some time by budding from the primary follicles; later in development the

sizee of the thyroid increases mainly by increasing the volume of the existing follicles (136).

1.3.. Thyrotropin Releasing Hormone (TRH).

Thee thyroidal secretory activity is regulated by the hypothalamic-pituitary unit through the

negativee feedback control mechanism via plasma FT4 and FT3 (Figure 6). The hypothalamic

hormonee TRH (a tripeptide) is synthesized in the paraventricular nuclei of the hypothalamus

Thyroidd gland

Figur ee 6: Schematic representation of the primary system off regulation of hypothalamic-pituitary-thyroid function. Thee fundamental actions are hypothalamic stimulation of thyrotropicc function balanced by the powerful negative-feedbackk inhibition exerted by thyroid hormones. +, stimulation;; -, inhibition.

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Generall Introduction

andd transported to the anterior pituitary via the hypothalamic-pituitary tract (portal vessels).

InIn addition to the role as a releasing hormone for TSH (and PRL), TRH also functions as a

neurotransmitterr in several parts of the brain (67,1 51).

1.4.. TSH Synthesi s and Secretion . Fromm the thyroidologist's perspective the pituitary gland is the conductor of the endocrine

orchestraa in which the thyroid gland plays the first violin. The thyrotropes in the anterior

pituitaryy synthesize and secrete TSH under the stimulating influence of TRH, that stimulates

thee thyroid gland. Somatostatin and dopamine inhibit TSH synthesis. The negative feedback

mechanismm via plasma FT4 and FT3 plays a very important role in the control of TSH

synthesis.. TSH synthesis in the thyrotropes is suppressed by T3, once T3 binds to the

nuclearr thyroid hormone receptors (a1 & (32).

Thee TSH molecule is a heterodimer, whose a- and (3-subunits are noncovalently linked

(135).. TSH, LH, FSH, and hCG have their a-subunit in common, while the j3-subunits are

specificc for each of these hormones. Both types of subunits are synthesized in the pituitary

glandd under the influence of aforementioned hormones and transcription factors. For more

detailss on the molecular structure of TSH, see under the heading: I.8.1.

1.5.. Thyroi d Hormon e Receptor . Thyroidd hormone, to be more precise T3, acts via the nuclear T3-receptor. At least four

thyroidd hormone receptor isoforms exists. There are two T3-receptor genes located on

chromosomee 17 (a-gene) and chromosome 3 ((3-gene). Both genes have at least two

alternativee mRNA splice products (103). One of the products of the T3-receptor-cc gene

(a2)) does not bind T3 (15). The (31 and (32 T3-receptor forms and the a1 T3-receptor all

bindd T3 and are able to regulate transcription of thyroid hormone target genes, but they

differr in potency and affinity for T3 analogues (16).

Inn the absence of T3, thyroid hormone receptor binds together with one of several

corepressorr proteins, to DNA sequences genencally designated as thyroid hormone response

elementss (TREs) in the regulatory region of the target genes (126). The interaction of the

un-ligandedd receptor with DNA in general represses transcription of that particular gene

Thee binding of T3 causes a conformational change in the thyroid hormone receptor that

resultss in release of the corepressor and recruitment of coactivator proteins and as a result

genee transcription is activated (93). The TRE characteristically consists of two DNA hexamers,

termedd half-sites, with the consensus sequence AGGTCA. Often the half-sites form a direct

repeatt separated by four bases although the orientation of the half-sites to each other and

theirr spacing may vary considerably (180). Although T3-R may occupy the two half-sites as

homodimers,, available evidence suggests that the T3-R may preferentially form heterodimers

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inn the TRE with receptors for c/s-retmoic acid or other proteins (126).

Thee generation of several thyroid receptor isoforms knock out mice models, has greatly

enhancedd the understanding of the role of thyroid hormone receptors in development.

Thee milder overall phenotype of mice devoid of the T3 receptor binding receptor variants

comparedd to the debilitating symptoms of severe hypothyroidism indicates divergent

consequencess of receptor versus hormone deficiency (75).

Thee syndrome of resistance to thyroid hormone, characterized by diffuse goiter, varying

manifestationss of hypothyroidism, elevated plasma T3 and T4 levels, and normal (or elevated)

plasmaa concentrations of TSH, is associated with abnormalities in the T3-receptor-Fj-gene

(146).. Attention-deficit disorder (or Attention Deficit Hyperactivity Disorder = ADHD) is

foundd in as many as 60% of the affected children (81). See also under TSH

hyporesponsivenesss (11.1.2.2.1).

1.6.. lodothyronine Deiodinases.

Thyroidd hormone exerts important effects on cellular processes in multiple tissues. The

actionss of thyroid hormone appear to be tightly controlled by several regulatory mechanisms

likee in other hormonal systems, particularly those of the adrenal cortex and gonads, (155).

Cellularr processing governs the uptake and metabolism of T4 and T3. These processes

stronglyy influence plasma concentrations of T4 and T3 and are critical determinants of the

cellularr levels of T4 and T3 in individual tissues (156). Figure 7 shows how important these

tissue-specificc factors are in the regulation of the thyroid hormone levels; as determined by

Escobar-Morrealee et al. (60,61) the tissue contents of T4 and T3 vary remarkably among

400 -,

35 5

30 0

25 5

20 0

15 5

10 0

5 5

0 0

4 4 T-, ,

Mi l l II I i— i — i — i — i — i — i — i — i — i — i — i — i — i i <?? Li K P Cb Lu A O B H S Cx M

a. . Tissue e

Figur ee 7: Tissue content in the adult rat of T4 and T3 as expressed in nanograms per milliliter (plasma)) or nanograms per gram of tissue. Li. liver; K, kidney; P, pituitary; Cb, cerebellum; Lu, lung; A,, adrenal; O, ovary; B, brown fat; H, heart; S, spleen; Cx, cerebral cortex; M, skeletal muscle. Adaptedd from Escobar-Morreale et al. (From Thyroid Today, with permission from GEM Communications,, Norwalk, CT, USA).

20 0

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Generall Introduction

HH H o

HO-( II I V C - C - C Tyrosine

HH N H 20 H

// v H H ,0 HH H o

H 0 - / (( ) V c - C - C 3 Monoiodotyrosine

II "2

HH »

CC 3,5 Dnodotyrosine

HH N H , X H

II 2

II u u

I I

H 0 - < T j \ - 00 - / ( J V c - C - c ' 3',3,5-Triiodothvronine

HH NH2 0 H

II I H H

H O ^ ^ V o - U j V c - C - C ** 3',5',3.5Tetraiodo-y - VV ^ T V I I S0H thyronine jj I H N H 2 IThyroxine)

Figur ee 8: Structures of the major lodoamino acid derivatives found in thyroglobulin (From Braverman LE,, Utiger RD, eds. Werner & Ingbar's The Thyroid T~' ed. Philadelphia-New York, with permission fromm Lippincott Raven, Philadelphia, PA, USA).

organs.. For example, the T4 content of the liver is 10-fold higher than that of skeletal

muscle,, and T3 levels in the pituitary gland are significantly higher than in other tissues;

otherr studies confirm theses findings (172). Deiodination plays an important role in thyroid

hormonee metabolism (1 56).

T4,, which is the major secretory product of the thyroid gland (Figure 8), functions primarily

ass a prohormone and needs to be converted to T3 by iodothyronine deiodinase to exert its

biologicall activity (101,102,107). T3 has the highest affinity for the nuclear receptor and is

believedd to mediate most of the metabolic effects (16). The conversion of T4 to T3 occurs

inn the thyroid gland and other tissues by deiodination of the outer (phenolic) ring at the 5'-

orr 3'-position (Figure 9). Both T4 and T3 can also be deiodinated at the 5- or 3-position of

Conjugatio nn B h e r B o n ( J Dominat io n bultat ee Cleavag e Decarboxylatio n Glucurontde e

i tt 11 T 44 H O ^ g > - 0 - ^ p ) > - C H - C H - C 0 2 H

N H 22 Figur e 9: Metaboli c pathway s fo r thyroi d outerr I 5 5 I inner hormon e metabolis m (From Thyroid Today,

„„ . _, . with permission from GEM Communications, Deiodinatio n n

Norwalk,, CT, USA).

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Chapterr 1

thee inner (tyrosyl) ring to form reverse T3 (rT3), which appears to have no known metabolic

activity,, and 3,3'-T2, respectively, which along with 3,5-T2 may have direct effects on

mitochondriall function (118). Although iodothyronmescan be metabolized otherwise, such

ass by conjugation to sulfate or glucuronate, or by deamination and decarboxylation to

formm tetraiodothyroacetic acid (tetrac, from T4) or triiodothyroacetic acid (triac, from T3),

approximatelyy 80% of T4 is metabolized by deiodination (156,58)

Twoo different enzymes have been demonstrated for the iodothyronine deiodinase to catalyze

T44 activation. Type I iodothyronine deiodinase (ID-i) is present in thyroid gland, liver, kidney,

andd many other tissues. Type II iodothyronine deiodinase (ID-II) is present in brain, anterior

pituitary,, brown fat, pineal gland, placenta and Harderian gland in the rat (101,102,107,162)

andd recently also demonstrated in muscle tissue (83). For details of iodothyronine deiodmases

seee Table 1. ID-I activity is known to decrease in the hypothyroid state and is believed to

havee a primary role in maintaining the circulating T3 levels (101,102,107). ID-II activity, in

contrast,, increases in the hypothyroid state and plays a critical role in providing the local

intracellularr T3 (101,107).

Tabl ee 1: CHARACTERISTICS OF IODOTHYRONINE DEIODINASES

ID-11 ID-2

ReactionReaction catalyzed 5' or 5 deiodination 5' deiodination

ID-3 3

55 deiodination

Location Location

SubstrateSubstrate preference

Inhibitors Inhibitors PTU PTU lopanoiclopanoic Acid

Selenocyst&ine Selenocyst&ine

ChromosomeChromosome Location

FactorFactor stimulating activity

liver,, kidney, thyroid,, pituitary

5'' : rT3 >T2S >T4 55 ; T4S >T3S

++++ + +++ +

present t

1p32-p33 3

thyroidd hormones TSH H

androgens s

sr,, kidney: decrease

pituitary,, brain, brownn fat, thyroid*,

heart*,, skeletal muscle*

T44 >rT3

+ + ++++ +

present t

14q24.3 3

growthh factors phorboll esters

catecholamines s

alll tissues: increase

brain,, skin, uterus,, placenta,

fetus s

T3>T4 4

V--+++ +

present t

14q32 2

thyroidd hormones growthh factors phorboll esters

retinoids s

brain:: decrease thyroid:: increase

*humann only

Adaptedd after St. Germain, DL in Thyroid Today, vol. XXII, number 3, 1999.

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1.7.. Thyroida l Iodin e Metabolism . Thee fact is that humans have an extraordinary high and truly dramatic dependence on

iodinee (22). Iodine may be classified as a trace element: Wolf described the thyroid gland

ass 'an efficient collector of a trace element' (165,181). A widely held tenet of physiology is

thatt iodine exerts all its effects through the thyroid. A possible exception is iodine's role in

improvingg or preventing mammary dysplasia. Iodine can also work with myeloperoxidase

too inactivate bacteria in vitro, and a similar effect in vivo is likely. However, the overwhelming

importancee of iodine lies in its being an essential component of thyroid hormone. Iodine

deprivationn early in intra-uterine life causes a person to become - to put it bluntly and

dramaticallyy - a mentally retarded, deaf-mute dwarf with major neurological defects and

goiterr ("cretin").

Iodinee enters the thyroid follicular cells as iodide (I) and is transformed through a series of

metabolicc steps into the individual hormones T4 and T3. Iodide is an essential component

inn the synthesis of the principal thyroid hormones, T4, and T3, contributing to 65% and

59%% of their respective molecular weights (49). In order to meet the demand for adequate

amountss of thyroid hormone, the thyroid has developed through evolution an elaborate

mechanismm for concentrating iodide from the circulation and converting it into thyroid

hormone.. The thyroid hormones are stored and released into the circulation when needed.

Moreover,, as demonstrated in Chapter 2 of this thesis, the fetal thyroid has the potential

too accumulate enough iodide for producing sufficient amounts of T4 (T3) during the neonatal

period.. This will only happen when the mother has a sufficient iodine intake during

pregnancy. .

Thee active transport of iodide into the thyroid follicular cell is dependent on the presence

off a NaV I symporter (NIS) (21,31,1 53). Further processing involves the covalent binding

off iodine to tyrosine residues (iodide organification) within the Tg molecule and their

subsequentt coupling to form thyroid hormone. The enzyme responsible for tyrosine

iodinationn and coupling is thyroid peroxidase (TPO), a glycoprotein located on the apical

membranee of the thyroid follicular cell (165). TPO activity requires the presence of hydrogen

peroxidee (H202) generated by two recently cloned thyroid oxidases (51,129). TPO and

especiallyy the TPO gene are discussed in detail in Chapters 4 and 5.

Iodin ee Deficienc y Disorders .

Iodinee deficiency is the world's most common endocrine disease, the most common

preventablee cause of mental retardation, and the easiest of the major nutritional deficiencies

too correct (48). Globally, iodine as a natural resource is extremely scarce in many areas and

endemicc goiter and cretinism caused primarily by insufficient supply of iodine remain a

majorr health problem for many populations (Figure 10). Iodine deficiency still often leads

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Currentt Status of Iodine Deficiency Disorders Globall Distribution - January, 1995

Basedd on Total Goiter Rate in School-age Children

Statuss of IDD

IDDD Eliminated KiR

§§ff Mil d m n i T OB i-2l)

ggg Mrjd.-rafc Mil. K.I - 2

££ Severe IDDiTGR :i(i

:'. IDDstaluab ins del

Figur ee 10: Current status of iodine deficiency disorders (IDD). Global distribution, January 1995, basedd on the total goiter rate (TGR) in school-age children. Data from CIDDS database (USAID/ ICCIDD/UNICEF/WHO).. From Dunn JT, Thyroid Today, with permission from GEM Communications, Norwalk,, CT, USA).

too various degrees of impaired brain development, mostly in populations of children living

inn poor regions (168). The World Health Organization estimates that 1.8 billion people

(approximatelyy 30% of the world's population) are at risk for iodine-deficiency disorders

(IDD),, 750 million people suffer from goiter, and more than 5 million suffer from cretinism

MM 83). The data nresented in Table 2 a!thounh from the same author demonstrate slicihtly

differentt numbers probably because the data are from a different year. Such public health

problemss could be soived relatively easily if all salt consumed in affected areas were iodized,

Tabl ee 2: Population living in areas at risk of iodine deficiency disorders and affected by goiter* (Fromm Braverman LE, Utiger RD, eds. Werner & Ingbar's The Thyroid 7tn ed. Philadelphia-New York, withh permission from Lippincott Raven, Philadelphia, PA, USA).

WHOO Regions

Africa a

Americas s

Easternn Mediterranean

Europe e

Southeastt Asia

Westernn Pacific

TOTAL L

Population n (millions) )

550 0

T T

406 6

847 7

1355 5

1553 3

5438 8

Populationn at Riskk of IDD

MILLION S S

181 1

168 8

173 3

141 1

486 6

ff 23

1572 2

% %

32.8 8

23.1 1

42.6 6

16.7 7

35.9 9

27.. i

28.9 9

Population n byy Goiter

MILLION S S

86 6

63 3

93 3

97 7

176 6

141 1

655 5

Affected d

% %

15.6 6

8.7 7

1111 9

11.4 4

13.0 0

9.0 0

l i . a a

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ass has been done in several countries. However, the sociopolitical realities of many of the

affectedd regions have prevented solutions like this from being implemented.

Thee consequences of iodine exces s are also discussed under transient hypothyroidism. A

veryy recent study from Denmark, a country with mild iodine deficiency, suggests that the

fetall thyroid, at least in areas of mild iodine deficiency, is more sensitive to the inhibitory

effectt of iodine than hitherto anticipated. Maternal iodine supplementation caused an

increasee in cord blood TSH (122).

1.8.. Thyroi d Determinant s in Plasma . Thee following plasma thyroid determinants play a major role in the etiologic diagnosis of

CHH and are specifically outlined. Plasma FT4 and at a later point in time plasma TSH also

playy a major role in assessing the correct T4 dosage during treatment for CH (chapter 3).

Thee sources of reference values for thyroid determinants in neonates and children are

limitedd (65,119,124), see also Table 3.

Tabl ee 3. Age-related normal values of plasma FT4 and TSH concentrations (adapted from Nelson, Clark,, Borut, Tomei, Carlton [13])

Age e

Cordd plasma 11 -4 days 2-200 weeks 5-244 months 2-77 years 8-200 years 21-455 years

FT44 (pmol/l)* 2SDD - +2SD

9.00 - 17.2 28.33 - 68.2 11.22 - 29.6 10.33 - 23.2 12.99 - 27.0 10.33 - 24.5 11.66 - 32.2

FT4FT4 (ng/dl) -2SD-2SD - +2SD

0.70.7 - 1.3 2.22.2 - 5.3 0.9-2.3 0.9-2.3 0.8-0.8- 1.8 1.0-2.1 1.0-2.1 0.8-0.8- 1.9 0.9-2.5 0.9-2.5

TSH H -2SD D

<2.5--1.0 0 1.7 7 0.8 8 0.7 7 0.7 7 0.4 4

mU/l) ) -- +2SD

-- 17.4 -39.0 0 -- 9.1 -- 8.2 -- 5.7 -- 5.7 -- 4.2

** To convert the plasma FT4 concentration to ng/dl, multiply by 0,0777.

Age-relatedd reference values of plasma FT4 and TSH concentrations (From Vulsma T & De Vijlder JJM.. Thyroid diseases in newborns, infants and children. Oxford Textbook of Endocrinology, chapter 3.4.8,, with permission from Oxford University Press, Oxford, UK).

1.8.1.. TSH

Pituitaryy thyrotropin or thyroid stimulating hormone (TSH) is one of four related glycoprotein

hormoness synthesized by the anterior lobe of the pituitary gland (TSH, FSH and LH) and by

thee placenta (hCG). TSH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and

humann chorionic gonadotropin (hCG) consist of two noncovalently linked a- and p1 subunits

(182).. The amino acid sequence of the rj.-subunit is common to all four glycoprotein

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hormoness within one mammalian species. The fj-subunit has a different amino acid sequence

inn each hormone and carries specific information relating to receptor binding and expression

off hormonal activity. The carbohydrate structure of the P-subunits may vary among the

fourr hormones due to differences in conformation induced by different P-subunits, or

becausee of various carbohydrate processing enzymes present in different cells of the pituitary

andd placenta (77,78). The free P-subunit is devoid of bioactivity and requires noncovalent

combinationn with the common a subunit to express such information.

Plasmaa TSH concentrations are the result of the balance between synthesis/release and

metabolicc clearance (29). The metabolic clearance rate of plasma TSH secreted after TRH

stimulationn has a half-life of 46-102 minutes (125). The plasma half-life of both exogenously

administeredd bovine and recombinant human TSH in adults is circa 30 minutes (6,27). In

Chapterr 3, we describe the comparatively extremely prolonged 50% reduction time of TSH

inn neonates with CH after initiation of T4 supplementation, which is more than 3 days; this

Chapterr gives additional explanations for this phenomenon.

1.8.2.. Thyroxin e (T4).

T44 is the major secretory product of the thyroid gland and can be considered as the

prohormonee of the more active T3 (Figure 11). More than 99% of T4 is bound to plasma

Hypothalamus s

Pituitaryy gland

Thyroidd gland

Periphery y

FT,, • FT,

Figur ee 11: Schematic representation of the primaryy system of regulation of hypothalamic-p i tu i tary- thyro idd func t ion . The major productionn of thyroid hormone from the thyroidd gland is T4, which is converted to T3. Bothh hormones are bound to transport proteins. .

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bindingg proteins (see also 1.8.5). The generally accepted model for thyroid hormone action

iss that T4's principal function is to serve as a buffer and precursor for T3 in the deiodination

off T4 by iodothyronine deiodinases (IDs) (126,127). The hypothesis holds that T3 is bound

too the nuclear receptors (T3-R) with higher affinity than T4.

1.8.3.. Triiodothyronin e (T3).

Triiodothyroninee (T3) is the active compound that binds to the nuclear receptor. Interaction

off the hormone with the receptor initiates a cascade of nuclear events that result in the

augmentationn or inhibition of expression of those genes to which the T3-T3R complex

binds.. Like T4, most of T3 (>99%) is bound to plasma binding proteins, but its affinity for

thee proteins is less than that of T4. Only some T3 is synthesized in the thyroid gland, but

mostt of plasma T3 is derived from deiodination of T4 (24), see also section 1.6. One of the

benefitss derived from the peripheral conversion of T4 to T3 is that the slower fractional

turnoverr of T4 compared with that of T3 helps to stabilize the level of circulating T3. The

levell of plasma T4 plays an additional role in thyroid hormone homeostasis.

Inn CH we often find that plasma T3 concentrations are less decreased than plasma T4,

especiallyy in the more severe forms of CH.

1.8.4.. Free Thyroxin e (FT4)

Freee thyroxine (FT4) is the small portion of T4 that is not bound to the three thyroid

hormonee binding proteins: thyroxine binding globulin (TBG), transthyretin (TTR), and

albumin.. Plasma FT4 is a very useful determinant in the clinical setting, especially in conditions

wheree the plasma TBG concentration is outside the normal range. Decreased TBG levels

aree not uncommon in The Netherlands. In neonates with TBG deficiency, where total

plasmaa T4 is decreased and plasma T5H is normal, plasma FT4 is most helpful in the

diagnosticc process.

Duringg the first phase of treatment for CH (usually a few weeks), plasma FT4 is the most

usefull determinant for assessing whether euthyroidism has been reached after initiation of

T44 supplementation and whether T4 supplementation dosage is adequate (this thesis,

Chapterr 3).

Severall methods for FT4 determination exist. Immunoassays are most frequently used and

seemm to measure lower values of plasma FT4 than dialysis methods (14, 66). Bongers-

Schokkmgg et al. (13) measured in children during the neonatal period in the same samples

byy dialysis method plasma FT4 concentrations of 50 - 75 pmol/L, while by FT4 immunoassay

concentrationss of 28 - 68 pmol/L were found. Because dialysis methods are labor intensive

andd expensive, these methods are less practical for routine measurements. For reference

valuess of the different thyroid determinants see Table 3 (179).

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Tabl ee 3. AGE-RELATED NORMAL VALUES OF PLASMA FT4 AND TSH CONCENTRATIONS (ADAPTED FROMM NELSON, CLARK, BORUT, TOMEI, CARLTON)

Ag e e

Cordd plasma 1-44 days 2-200 weeks 5-244 months 2-77 years 8-200 years 21-455 years

FT44 (pmol/l) * -2SDD - +2SD

9 . 0 -- 17.2 28.33 - 68.2 11.22 - 29.6 10.33 -23 .2 12.99 - 27.0 10.33 -24 .5 11.66 -32 .2

FT4FT4 (ng/dl) -2SD-2SD - +2SD

0.70.7 - 1.3 2.22.2 - 5.3 0.9-2.3 0.9-2.3 0.8-0.8- 1.8 1.0-2.1 1.0-2.1 0.8-0.8- 1.9 0.9-2.5 0.9-2.5

TSH H -2SD D

<2.5 5 1.0 0 1.7 7 0.8 8 0.7 7 0.7 7 0.4 4

(mU/l ) ) -+2SD D

-- 17.4 -- 39.0 -- 9.1 -- 8.2 -- 5.7 -- 5.7 -- 4.2

Too convert the plasma FT4 concentration to ng/dl, multiply by 0,0777.

Tabl ee 3: Age-related reference values of plasma FT4 and TSH concentrations (From Vulsma T & De Vijlderr JJM. Thyroid diseases in newborns, infants and children. Oxford Textbook of Endocrinology, chapterr 3.4.8, with permission from Oxford University Press, Oxford, UK).

1.8.5.. Thyroxin e Bindin g Proteins .

Threee human transport proteins for thyroid hormone exist, namely: thyroxine binding

globulinn (TBG), transthyretin (TTR) and albumin (Figure 12). These circulating transport

proteins,, which are the delivery system for thyroid hormone vary widely in concentration,

andd affinity for thyroid hormone. The net result is that more than 99% of the circulating

Serum m

Cell l

Bindingg prote ins

T44 T3

tt I Freee T. and free T,

Figur ee 12: Thyroid hormone transport in plasma andd cellular hormone action. The binding proteinss include thyroxine-binding globulin, transthyretin,, and albumin. TR denotes the thyroidd hormone (T3) receptor. (From Surks MJ, Sievertt R. 1995 Drugs and thyroid function. N Engll J Med. 333:1690, with permission from Thee New England Journal of Medicine, Boston, MA,, USA).

hormonee is protein bound but is in constant equilibrium with FT4, which is available for a

rapidd entry into cells. TBG, a minor component of the a-globulins, carries about 70% (in

healthyy adults) of the circulating T4 and T3 by virtue of its high affinity for the two hormones

(T44 > T3); it has no other known physiologic function. TTR, or thyroxine binding prealbumin,

bindss only about 10% to 15% of the hormones, but is responsible for much of the immediate

deliveryy of T4 and T3 to cells. The affinity of TTR for T4 and T3 is lower and therefore they

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dissociatee from TTR more rapidly (147). TTR is the major thyroid binding protein in human

cerebrospinall fluid and in plasma in rats. Albumin, a protein that carries a multitude of

smalll molecules, binds 15% to 20% of the circulating T4 and T3 under normal euthyroid

conditions.. The affinity for T4 and T3 is lower than that of TTR, and the hormone-albumin

complexess dissociate very rapidly (147). TBG levels greatly influence T4 and T3 levels, and

needd to be measured for a sound assessment of thyroid function.

TBGG deficiency is not rare and can cause very low levels of both plasma T4 and T3. Because

T44 is measured in heelpuncture blood, TBG deficiency can cause false positive screening

results.. TBG deficiency can be partial or complete; the latter is found only in males, which

iss understandable because the TBG gene is located on the X-chromosome. Since an additional

TBGG determination in heelpuncture blood has been introduced (since 1995), the amount

off false positive CH screening results in the Netherlands has considerably decreased.

1.8.6.. Thyroglobulin (Tg).

Tgg is the predominant homodimeric glycoprotein (660 kDa) of the thyroid gland (112),

functioningg as a matrix protein in thyroid hormonogenesis. Catalyzed by the enzyme TPO,

tyrosinee residues in the Tg molecule are iodinated, and subsequently specific molecules are

coupledd to form mostly T4 and some T3 (39,47). The human Tg gene that is located on

chromosomee 8 (8q24.2-8q24.3) measures over 300 kb and contains 48 exons (4,5,164). The

Tgg mRNA has 8307 nucleotides of coding sequence, of which 66 triplets/codons encode a

tyrosinee residue (169). In view of the key function in thyroid hormonogenesis, it is to be

expectedd that mutations in the Tg gene can cause CH and indeed autosomal recessive

mutationss in theTg gene are described (170), see also Tg synthesis defect (section 11.1.2.2.4).

Plasmaa Tg levels are high in the neonatal period when compared to adult levels. Factors

likee respiratory distress in preterm neonates can influence Tg levels (91). Plasma Tg declines

graduallyy over the first year of life (87). Plasma Tg levels is a very useful determinant in the

etiologicc diagnostic process. In general plasma Tg is more elevated in most forms of thyroid

dyshormonogenesiss than in thyroid dysgenesis. Plasma Tg levels are related to the amount

off thyroid tissue present (in cases of dysgenesis) and the level of plasma TSH; plasma TSH

increasee leads to plasma Tg increase. In thyroid agenesis plasma Tg is undetectable, in

cryptopicc remnants it is very low, often despite very high plasma TSH levels. In the thyroid

dyshormonogenesiss Tg synthesis defect, plasma Tg is usually (but not exclusively) low (40).

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1.9.. Thyroi d Determinant s in Urine .

1.9.1.. Urinar y Iodin e excretion .

Urinaryy iodine excretion (UIE) is a reliable tool in assessing iodine status (145) and can be

easilyy applied to population studies (45). In the steady-state situation in adults a close

relationshipp between intake and excretion of iodine exists. In neonates an equilibrium needs

too be established with a temporary negative or positive iodine balance as a result (see Chapter

2).. To assess transient hypothyroidism due to iodine excess, UIE is an excellent determinant.

1.9.2.. Urinar y LOMWIOM excretion .

Loww molecular weight iodinated material (LOMWIOM) consists of a spectrum of

iodopeptidess (76), which are sometimes excreted in the urine of CH patients (76,92).

Absencee or presence of these peptides in the urine is helpful in making the etiologic

diagnosis,, for instance they are often detected in the urine of patients with the

dyshormonogenesis:: thyroglobulin synthesis defect. However, other defects like PIOD and

sometimess dystopic thyroid remnants, can also give extra (urinary) excretion of LOMWIOM

(Dee Vijlder, personal communication).

1.10.. Maternal-Feta l Transfe r of Thyroi d Hormone . Thee role of maternal thyroid hormone in fetal brain development is an important issue

(42),, that is complicated by the variable extent of placental permeability to thyroid hormone

amongg species studied (64,126). Differences result from structural features of the placentas,

ass well as variability in concentrations of placental iodothyronine deiodinase activities (52,64).

Earlyy studies suggested that maternal thyroid hormone could not cross the placenta.

However,, there is now convincing evidence of transplacental transport of thyroid hormones

inn rats (117,123). T4and T3, derived from the mother by placental passage, were detected

inn rat embryos before the secretion of the fetal thyroid began on embryonic day 17

(116,123,140).. In contrast there is only very limited transfer of maternal thyroid hormone

too the fetus in sheep (64).

Vulsmaa et al. (176) demonstrated that in human fetuses with severe CH, maternal-fetal

transferr of T4 results in cord plasma T4 levels 25-50% of those in normal neonates, despite

highh iodothyronine deiodinase type III (ID-Ill) activity (95,162). Since ID-II activity in the brain

increasess in response to decreased concentrations of T4, as demonstrated in rats (105,106),

thesee levels of T4 might suffice as substrate to maintain normal or near normal T3

concentrationss in brain but not in other tissues (20). This would account for the finding that

mostt of the CH children have normal intellectual development if treated promptly after birth

(14,50). .

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1.11.. Neonata l CH Screening . Inn the Netherlands, the screening method for CH (heel puncture about 5 days after birth)

iss primarily based on determination of T4, with additional TSH determinations in the 20%

sampless with the lowest T4 concentrations (175). In order to prevent too many false positive

screeningg results, a TBG determination is added in the 5% samples with the lowest T4

concentrations;; a T4/TBG ratio is then calculated. The advantage of the Dutch T4-based

screeningg program is the capability to detect both thyroidal (primary) and central (secondary/

tertiary)) CH (174). As mentioned earlier, the incidence of primary permanent CH in the

Netherlandss is 1:3100 newborns, and the incidence of central CH (or CTDS = Congenital

Thyrotropinn Deficiency Syndrome) is 1:20,000 (40). Inborn errors of thyroid hormone

metabolismm are found 1:18,000 live newborns.

Fromm a number of international screening reports, it can be estimated that in areas without

endemicc iodine deficiency, the mean incidence of permanent primary CH is roughly 1:

3,5000 newborns (80,167). Considerable ethnic differences are present with the extremes:

1:30,0000 among African-Americans in the United States (17), and 1:900 among certain

populationss from Asian descent in the United Kingdom (149).

.. Thyroi d pathology , especiall y the etiologi c classificatio nn of CH.

Thyroidd diseases in infants and children can be divided into three major groups:

•• Congenital hypothyroidism.

•• Auto-immune thyroid disease, causing hyper- and hypothyroidism, and goiter with or

withoutt thyroid dysfunction.

•• Thyroid neoplasia.

Alll three diseases can present with goiter, although goiter in neonatal hypothyroidism due

too CH is rare (personal observation). Hyperthyroidism and thyroid tumors are beyond the

scopee of this thesis. Hypothyroidism in children can be defined in several ways:

•• Congenital or acquired7

•• Is the disorder permanent or transient7

•• What is the level of the disorder

1.. thyroid = primary

2.. pituitary = secondary

3.. hypothalamus = tertiary

Inn this introduction and thesis, only congenital hypothyroidism will be discussed. Acquired

hypothyroidismm is usually due to an auto-immune thyroid disease, like Hashimoto's disease

(69). .

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Tabl ee 4: CLASSIFICATION OF DISORDERS CAUSING PERMANENT CONGENITAL HYPOTHYROIDISM ACCORDINGG TO THE CLINICO-PATHOLOGIC CHARACTERISTICS

Diagnosti cc determinan t

Etiologi cc Entit y

Plasm aa FT4 concentratio n n

Plasm aa TSH concentratio n n

Plasm aa Tg concentratio n n

Urinar y y excretio nn of iodopeptide s s

HYPOTHALAMIC/PITUITAR YY CONGENITAL HYPOTHYROIDISM (SECONDARY AND TERTIARY CH) t Hypothalamicc and/or pituitary Low Low to Low Nl dysgenesiss increased

Hypothalamic/pituitaryHypothalamic/pituitary dyshormonogenesis TRHH hyporesponsiveness Low TSHH deficiency Low TSHH hypoactivity Low to normal

Low w Low w (Slightly) ) increased d

Low w Low w Loww to normal

Nl l Nl l Unknown n

THYROIDALL CONGENITAL HYPOTHYROIDISM (PRIMARY CH) ThyroidThyroid dysgenesis

Thyroidd agenesis Cryptopicc thyroid remnant Dystopicc thyroid remnant Eutopicc thyroid remnant

ThyroidThyroid dyshormonogenesis TSHH hyporesponsiveness

TSHRR deficiency Gsaa deficiency

Totall iodide transport defect Totall iodide organification

defect t Partiall iodide organification

defect t Pendred'ss syndrome***

Thyroglobulinn synthesis defect Iodidee recycling defect

(syn:: dehalogenase defect)

*lnn case a newborn infant cannot produce any T4, maternal-fetal transfer is responsible for T4

concentrationss of 2.7-5.4 mg/dL (35-70 nmol/L) in cord serum, which disappear with a half-life of 2.7-5.33 days. "("Thee most significant determinant for centra! hypothyroidism is MRI of the cerebral midline structures; thee TSH response to intravenously administered TRH may discriminate between defects of hypothalamicc or pituitary origin. ## Na'231 is administered intravenously (1 MBq [27 mCi] for infants younger than 1 year and 2 MBq [544 mCi] for older children). In general, the radioiodide uptake is a function of the amount of thyroid tissuee and the degree of stimulation by TSH. **Sodiumm perchlorate is administered intravenously 2h after Na'23l (10 mg/kg body mass, max. 400 mg).. Discharge of thyroidal radioiodide after 1 h:

Absentt * Absentt * Loww to normal Loww to normal

Loww to normal Normall to low (Very)) low Absent* *

Loww to normal

Normall to low Loww to normal Loww to normal

Veryy high Veryy high (Very)) high (Very)) high

High h Normall to high Veryy high Veryy high

High h

Normall to high High h High h

Absent t Loww to normal Loww to high Unknown n

Loww to normal Loww to normal Veryy high Veryy high

(Very)) high

Normall to high Absentt to normal (Very)) high

Absent t Absent t Absentt to low Absentt to low

Unknown n Absent t Absent t Absent t

Absentt to low

Absent t High h Presencee of MITT & DIT

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(adaptedd from the DeVijIder JJM and VulsmaT (reference 40 Introduction) [from: Thyroid diseases in newborns, infants and children.. Oxford Textbook of Endocrinology, chapter 3.4.8, with permission from Oxford University Press, Oxford, UK].

Thyroi dd imaging ; locatio nn and size

Radioiodid e e uptak ee in th e thyroi dd #

Radioiodid e e releas ee afte r NaClO,, * *

Mod ee of Inheritance* * *

Normall to hypoplastic Nl l Nl l Autosomall recessive or dominant,, up till now restrictedd to subgroups off patients

Normall to hypoplastic Normall to hypoplastic Unknown n

Nl l Nl l Loww to normal

Nl l Nl l Absent t

Autosomall recessive Autosomall recessive Autosomall recessive

Absent t Absent t (Sub)lingual l Hypoplastic c

Normall to hypoplastic Normal l Normall to hyperplastic Normall to hyperplastic

Absent t Absent t Loww to normal Loww to normal

Low w Lowl l Absentt t t Rapidd and high

Absent t Absent t Absent t Absent t

Absent t Absent t Absent t Total l

Autosomall recessive or dominant,, up till now restrictedd to subgroups off patients

Autosomall recessive Autosomall dominant Autosomall recessive Autosomall recessive

Normall to hyperplastic High

Normall to hyperplastic Normall to hyperplastic Normall to hyperplastic

Partial l Autosomall recessive

Normall to high Rapidd and high High h

Partial l Absent t Absent t

Autosomall recessive Autosomall recessive Autosomall recessive

<10%% is normal; 10%-20% is borderline; >20% is abnormal. IJMostt characteristic determinant for the diagnosis (total) iodide transport defect is the (very) low saliva/serumm ratio of radioiodide: for neonates >10 is normal, 3-10 is borderline, <3 is abnormal. Thee saliva/blood ratio is 1.17 times the saliva/serum ratio (95% confidence interval, 1.15-1.19). Partiall iodide transport defect is an ill-defined condition; if it exists, the diagnostic determinants entirelyy depend on the iodine intake, which varies greatly worldwide. ##Whenn the full-blown disease has an autosomal recessive pattern of inheritance, some heterozygous relativess have mild abnormalities in the relevant tests. ***Thee most significant determinant for Pendred syndrome is the sensorineural hearing defect. MIT,, monoiodotyrosme; DIT, diiodotyrosine; Nl, no indication for this test.

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11.1.. Permanen t Congenita l Hypothyroidism . Congenitall hypothyroidism is one of the most common causes of mental retardation that

cann be prevented by early institution of thyroid hormone supplementation. The incidence

off permanent primary CH in the Netherlands is circa 1:3100 newborns (178); yearly around

600 - 70 patients are detected by the Dutch neonatal CH screening. Most cases are due to,

usuallyy not hereditary, faulty embryonic development (disturbances in thyroid ontogeny).

Upp to 20% are caused by inborn errors of thyroid hormone synthesis (dyshormonogeneses),

thee dyshormonogeneses are hereditary disorders, and are mostly transmitted in an autosomal

recessivee way. In The Netherlands annually 8 - 1 0 newborns with non-thyroidal congenital

hypothyroidismm (secondary/tertiary hypothyroidism or CTDS) are detected through the CH

screeningg program.

CHH in neonates is not easy to recognize by symptoms and signs. Thus, in 1981 a nationwide

neonatall CH screening program was introduced in The Netherlands. CH screening programs

hadd already begun several years earlier in North America.

Permanentt congenital hypothyroidism can be categorized according to the level of disorder

(40)) as outlined in this section, see also Table 4.

11.1.1.. Centra l CH (Hypothalami c or Pituitar y CH).

II.II. 1.1.1. Defects in the TRH Receptor.

Centrall CH with complete absence of TSH and prolactin responses to TRH has been described

(28).. In this article the affected patient presented with growth retardation at the age of

almostt 9 years; plasma T4 was low (52 nmol/L) and plasma TSH was in the normal range

(1.33 ml i /L). Retrospectively, the CH screening turned out to have the same combination of

loww T4 (64 nmol/L) and normal TSH (13 mU/L) concentrations. Due to the fact that the CH

screeningg was TSH-based, the patient was not detected in the neonatal period. Plasma

TSHH and PRL did not rise after the intravenous administration of TRH. Molecular studies

revealedd different inactivating mutations in each allele (compound heterozygosity) of the

genee for the G-protem-coupled TRH receptor that resulted in formation of biologically

inactivee receptors unable to bind TRH.

II.II. 1.1.2. Defects in the Regulation of TSH Synthesis and Secretion.

Ass discussed in section 1.1, one possibility for a defect in the regulation of TSH synthesis is

thee combined deficiency of TSH, growth hormone (GH), and PRL, which is described in

patientss with mutations in the POU1 F1 gene (encoding for a pituitary transcription factor).

Thee patient described in Chapter 6 is compound heterozygous because of two different

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andd newly described mutations in the POU1F1 gene.

Anotherr type of combined pituitary hormone deficiency (CPHD) is caused by homozygous or

heterozygouss mutations in the transcription factor PROP1. PROP1 gene mutations not only

causee TSH, growth hormone, and PRL deficiencies in humans, but also LH and FSH deficiency.

Severall mutations have been described in other research (148,184), reviewed by Parks (128).

POU11 F1 and PROP1 are not the only transcriptior factors, for more information on pituitary

transcriptionn factors see under section 1.1.

//.. 1.1.3. Defects in TSH Synthesis.

Hereditaryy pituitary disorders exclusively concerning the synthesis of TSH are seldom found

(40);; an important question is whether these disorders are, in fact rare, or are missed

duringg the CH screening. Patients described with aberrant TSH have high serum TSH

concentrationss compensating the impaired biological activity (154), show minimal

hypothyroidismm and high serum TSH levels. At the same time, patients with completely

inactivee TSH caused by single base mutations (30) or deletions (143) show severe

hypothyroidismm with low plasma TSH concentrations. In three severely hypothyroid patients

withh totally inactive TSH, the defect was a 6ly29Arg mutation in the [Cys.Ala.Gly.Tyr.Cys]

regionn of the gene for the (5-subunit of TSH. The result is synthesis of f}-subunits that cannot

combinee with a-subunits (82).

11.1.2.. Thyroida l Congenita l Hypothyroidis m (= Primar y CH).

Detailss of different etiologies for thyroid developmental disorders and inborn errors of

thyroidd metabolism are listed in Table 4.

II.II. 1.2.1. Thyroid Dysgenesis

(Thyroid(Thyroid Developmental - or Embryonic Development Disorder).

Thee most important plasma determinants to assess the severity of CH are FT4 and TSH;

plasmaa Tg is necessary to assess the amount of thyroid tissue that is still present (agenesis

versuss dysgenesis, for instance). Imaging studies, especially the ' " I uptake study, will reveal

whetherr or not thyroid dysgenesis is present. More clinico-pathologic details of the different

formss of thyroid dysgenesis are listed in Table 4.

Overr the last decade molecular aspects of thyroid developmental problems have become

moree apparent (23,40). Research has demonstrated that the transcription factors TTF1,

TTF2,, and PAX8 are essential forr thyroid development, at least in mice (32,43,90,113,161),

andd consequently has led to investigation of patients with thyroid dysgenesis for the

occurrencee of aberrations in these transcription factors. Until now, one TTF1 mutation is

knownn to cause CH in humans (41). A homozygous missense mutation (Ala65Val) of TTF2

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hass been found in 2 siblings with a cleft palate, choanal atresia, and CH (26). A study of

1455 CH patients has revealed five patients who harbored monoallelic mutations in the

PAX88 gene (111); one patient had a dystopic thyroid remnant and the others a dysgenetic

eutopicc thyroid gland. Two cases were sporadic and three patients were familial; the latter

patientss were hypothyroid, and in contrast to the patient with dystopic thyroid tissue low

plasmaa Tg concentrations were found. The differently mutated PAX8 molecules were unable

too bind DNA and to activate gene expression (111).

II.II. 1.2.2. Thyroid dyshormonogenesis.

11.1.2.2.1.. Hyporesponsivenes s to T5H.

TSHH exerts its biological activity by binding to the TSH receptor, a glycoprotein containing

ann extracellular amino terminal domain, seven transmembrane domains, three extra- and

threee intracellular loops, and an intracellular carboxy-terminal domain (130). The receptor

iss a member of a super-family of G-protein coupled receptors. Activation of the receptor

throughh TSH binding leads to activation of G proteins. The activated Gsa-subunit stimulates

adenylyll cyclase, catalyzing the production of cAMP. The receptor can also activate the

oc-subunitt of the Gp protein, stimulating the phospho-inositol pathway, occurring mainly at

higherr TSH concentrations (109). Hyporesponsiveness to TSH may also occur through

mutationss in TSH, TSH receptor, G-proteins, or specific proteins or factors further downward

inn the signal-transducing pathway.

DefectsDefects in the TSH Receptor.

Mutationss in the TSH receptor causing loss of function, and resulting in congenital

hypothyroidism,, and other mutations causing gain of function, resulting in congenital non-

autoimmunee hyperthyroidism, have been described. (96,166). Among the patients with

losss of function mutations, the severity of the hypothyroidism is variable. For instance

mutationss in the extracellular domain of the TSH receptor that were found in siblings with

TSHH hyporesponsiveness (163), did not cause hypothyroidism, since the diminished binding

couldd be compensated by high TSH plasma concentrations. The high TSH level did not

resultt in exaggerated stimulation of thyroid metabolism and goitrogenesis was not observed.

Onn the other hand mutations in the TSH receptor, causing the absence of the receptor or

causingg strongly diminished binding of TSH (7,71) make the patient severely hypothyroid.

Thee complete lack of TSH stimulation represses almost completely the metabolic activity of

thee thyroid gland resulting in thyroid dysgenesis with low plasma Tg concentrations. The

inheritancee in all cases, except one, is autosomal recessive; usually compound heterozygosity

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iss involved, except for two families in which the defect was caused by homozygous mutations.

AbnormalitiesAbnormalities in the oc-Subunit of the G Protein.

Patientss with pseudohypoparathyroidism type 1a (Albright's hereditary osteodystrophy,

AHO)) (2,108) have another type of TSH hyporesponsiveness. AHO is a variably expressed

disorderr with autosomal dominant inheritance (34), characterized by short stature, skeletal

defects,, mental retardation and obesity. The patients have an approximately 50% reduction

inn the activity of the Gsa-subunit. In one of the alleles of the gene encoding for this protein,

locatedd on chromosome 20q 13, a variety of mutations have been found (186). The patients

havee often slightly elevated plasma TSH concentrations and low-normal levels of plasma

T4,, tending to a state of mild hypothyroidism. Although early detection by neonatal CH

screeningg has been described (108,178) the TSH and T4 concentrations will, in general,

nott reach the cut-off levels used in the neonatal CH screening programs. For that reason,

itt is likely that most patients with AHO will remain undetected by screening.

TSHTSH Hyporesponsiveness Caused by Other Factors.

Anotherr type of TSH hyporesponsiveness was described by Xie et al. (185); the search for

aa molecular biologic background in 3 families with TSH hyporesponsiveness did not reveal

aberrationss in TSH, the TSH receptor nor in the G-proteins. TSH hyporesponsiveness was

inheritedd in an autosomal dominant way in two families. Xie's study shows that several

genee products more distal in the TSH, TSH-receptor, G-protein signal pathway may be

involved. .

11.1.2.2.2.. Iodid e Transpor t Defect .

Thee first step in thyroid hormonogenesis is the active transport of iodide into the thyrocytes.

Activee iodide transport is not confined to the thyroid gland but also occurs in salivary

glands,, gastric mucosa, small intestinal mucosa, lachrymal gland, nasopharynx, thymus,

skin,, lung tissue, choroid plexus, ciliary body, uterus, lactating mammary tissue and placenta

(19).. One difference between iodide transport in the thyroid and the other structures is

thatt TSH regulates iodide transport only in the thyroid gland.

Iodidee transport defect (ITD) is a disorder caused by the inability to actively transport

iodidee into thyrocytes, which is the first step in the synthesis of iodine-containing thyroid

hormoness and is mediated by the Na '/\ symporter (NIS). In 1960, Stanbury wrote the first

clinicall description of ITD (157), but only recently mutations in the gene encoding for NIS

havee been described (70,110,137,138). To date, forty-two cases with ITD found in 25

familiess have been reported (98,129). The patients have in common mostly severe

hypothyroidismm with low or very low plasma T4 concentrations, high plasma Tg levels

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(177),, thyroid gland present on ultra-sound imaging, undetectable radio-iodide uptake by

thee thyroid gland, and a saliva/blood ratio of about 1 (40) (Table 4). The severity of

hypothyroidismm and neuro-developmental impairment nonetheless varies considerably,

probablyy as a result of variation in dietary iodine intake. These patients can be treated with

largee doses of iodine, or preferably with T4, especially in cases dealing with young children.

Sincee CH screening was introduced in The Netherlands, no patients with ITD have been

detected.. One contributing factor could be related to the idea that we are dealing with an

extremelyy rare condition. However, another possibility could be that patients are

misdiagnosedd with thyroid agenesis.

11.1.2.2.3.. Defect s in lodinatio n of Thyroglobuli n (Organificatio n Defects) .

Thyroi dd Peroxidas e Defect s (TIOD and PIOD).

Againn the first clinical description of this etiologic entity was by Stanbury (158). Several articles

THYROIDD PEROXIDASE GENE

F ^ = ^ ^

|| Frameshift mutation

\\ Mutation affecting splicing

Missensee mutation

00 1 Kb

Membranee spanning part

II Catalytic site

Figur ee 13: Overview of the mutations found in the TPO gene. For details, see chapter 4 (Adapted afterr a figure from Hennie Bikker, Academic Medical Center, University of Amsterdam, The Netherlands,, with permission).

reportt that thyroid peroxidase (TPO) activity in thyroid tissue of patients with a total iodide

organificationn defect (TIOD) is not detectable (120,8-12). TPO is a thyroid-specific glycosylated

hemoproteinn of 110 kD, bound to the apical membrane of the thyrocyte (165). The 933 amino

acidss containing protein is encoded by a mRNA of 3 kb (88). The TPO gene contains 17 exons,

iss 150 kb in size and located on chromosome 2, locus 2p25 (36,53,89). Absence of TPO activity

implicatess the inability to iodinate tyrosine residues in Tg and to couple these residues to form

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thyroidd hormones, mainly T4 and some T3 and rT3 (38,165). TIOD is inherited in an autosomal

recessivee way (10). Moreover, mutations in the TPO gene were described to be causative for

thee diagnosis TIOD (1,8,10). Chapter 4 describes the different TPO mutations detected in The

Netherlands,, in Figure 13 they are represented by arrows.

Annually,, approximately 3 patients with a TIOD are detected by the Dutch neonatal CH

screeningg program. Low T4 concentrations and elevated TSH levels in heel puncture blood

consistentlyy characterize the neonatal presentation. In addition extremely low plasma FT4

andd T4 levels, and high plasma TSH and Tg concentrations are detected. Another characteristic

iss the elevated radio-iodide ('23l) uptake by the thyroid gland with the immediate release of

alll accumulated radioiodine from the thyroid after intravenously administered sodium

perchlorate,, indicating the radiolabeled iodide cannot bind to protein (40).

AA partial iodide organification defect (PIOD) also exists and presents itself usually with a

lesss severe form of CH, for details see Table 4. PIOD can be a distinct clinical entity, or can

bee part of Pendred's Syndrome.

Pendred' ss Syndrome .

Inn 1898, Pendred described the association of goiter and congenital deafness (131), the

involvedd hypothyroidism turned out to be due to a partial organification defect. Pendred's

Syndromee is an autosomal recessive disease characterized by goiter, impaired iodine

organification,, and a moderate to severe sensorineural hearing loss since infancy (144).

Hypothyroidismm (usually mild) and goiter may be present at birth or may develop later in

life.. Pendred's Syndrome may be one of the most common hereditary metabolic disorders

causingg hypothyroidism, with an estimated prevalence between 1:15,000 - 1:100,000.

However,, only a few patients who suffer from this syndrome are detected by the neonatal

CHH screening program.

Thee gene mutated in Pendred's Syndrome (PDS gene) was recently cloned (62,72,73) and

encodess the putative chloride/iodide transporter pendrin (152). Mutations in the gene

encodingg for pendrin are described in other articles (97,173).

Forr a proper lodmation/organification of Tg not only TPO ts necessary. The synthesis of

thyroidd hormone is catalyzed by TPO in the presence of H,02 on the apical membrane of

thee follicular cells (121). In addition to TPO abnormalities, defective thyroidal iodide

organificationn could also result from defects in the generation of H202 (51). Recently the

H O-,, generating system has been characterized in more detail, two thyroid specific oxidase

geness named ThOX1 and ThOX2 have been cloned (34a). The H,0, generating system

workss in a Ca"/NAD(P)H dependent way (104a). Clinical implications of defects in the

thyroidd oxidase system are currently under investigation.

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Chapterr 4 demonstrates one family with the clinico-pathological picture of TIOD in whom

noo TPO mutations were found, as suggested in this chapter the cause for the disorder

couldd be related to the thyroid oxidases.

Figur ee 14: Neonatal goiter in a patient with a defectt in thyroglobulin synthesis, one of the inbornn errors of thyroid hormonogenesis (see sectionn 11.1.2.2.4 of the General Introduction). Neonatall goiter is a rare condition in The Netherlands s

11.1.2.2.. 4. Defect s in Thyroglobuli n Synthesis .

Thyroglobulinn (Tg) plays a central role in thyroid hormone synthesis by serving as a matrix

inn this process. The protein itself is relatively large (660,000 Da) and is synthesized exclusively

inn the thyrocytes. Through studies with Dutch goats we learned more about defects in

thyroglobulinn synthesis (35). Patients with Tg synthesis defects are moderately to severely

hypothyroid.. Usually, the plasma Tg concentration is low, especially in relation to the degree

off TSH stimulation (40). However, exceptions do exist, for example in a patient who had

highh plasma Tg concentrations, where all of the Tg was of low molecular weight (59).

Mostt patients with Tg synthesis defects have iodoproteins (mainly iodoalbumin) in their

serumm (37) and iodopeptides in their urine (76). The processes of iodide uptake, oxidation,

andd organification are intact and Table 4 shows more in detail the clinico-pathologic

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characteristicss that can be found.

Neonatall goiter which is often described by others in cases of thyroid dyshormonogenesis,

iss rare in The Netherlands, but recently a patient with a Tg synthesis defect presented with

ann obvious goiter (Figure 14).

Thee exceptionally large size of the Tg gene makes mutation identification difficult in the

regulatoryy or coding regions. However, a revised coding sequence for human Tg, which

wass published in 1997 (169) is a helpful tool in the study of the structure-function relationship

off Tg in thyroid hormonogenesis. Mutations in the Tg gene have been detected in only a

feww patients with CH (40). No mutations in Tg other than polymorphisms were detected in

sixx patients with CH in whom the clinical and biochemical findings were those of a Tg

synthesiss defect (170). These patients could have abnormalities in post-translational

processingg mechanisms. Only some of the cases described as Tg synthesis defect are the

resultt of aberrations in the primary structure of Tg (171). An overview of defects in Tg

synthesiss will soon appear in the thesis of Simone Van de Graaf (University of Amsterdam,

Academicc Thesis, 2000).

11.1.2.2.5.. Defect s in Recyclin g of Iodide .

lodotyrosiness (DIT and MIT) are deiodinated by specific dehalogenase(s) to monoiodotyrosine

(MIT)) and tyrosine, an activity not only present in the thyroid gland but also in peripheral

tissues.. Hereditary disorders in this deiodinating system lead to the loss of iodotyrosines

obtainedd after proteolysis of Tg in the thyroid, and which are then secreted into the

circulation,, and hence rapidly excreted by the kidney. The result is excessive renal loss of

iodinee in the form of MIT and DIT, mimicking hypothyroidism due to iodine deficiency

(25,85,86,159).. The disease is extremely rare; while a handful of patients are suspected

butt not confirmed of having an iodide recycling defect since the initiation of the Dutch CH

screeningg program (1981), only one patient has been proven to have this condition.

Patientss with defects in the recycling of iodine have a high to very high initial radioiodide

uptake,, followed by a relatively rapid decline, because the iodotyrosine molecules freed by

hydrolysiss of Tg are not deiodinated; as a result, no iodine is released within the thyroid

follicularr cells for recycling via oxidation and organification (40). The wasting of iodotyrosines

fromm the thyroid, which is increased by the high TSH secretions, may lead to an extremely

loww thyroidal iodine content (25). The inheritance of this defect is autosomal recessive, but

somee features of the disorder are expressed in heterozygous relatives, for example,

goitrogenesis,, a relatively high radioiodide uptake, and increased urinary DIT excretion

(115).. The clinical expression depends strongly on the iodine content of the diet, which

mayy explain why autosomal-dominant inheritance has been suggested (86).

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11.2.. Transient CH.

Transientt CH can be due to:

•• Iodide excess due to pre-, pen- or postnatal exposure.

•• Inhibiting maternal anti-thyroid immunoglobulins (114,1 39,141).

•• Maternal anti-thyroid medication.

•• Transient hypofunction in the premature neonate.

III.. Diagnosi s of CH.

Forr the initial diagnostic process in CH the following tests are used:

•• Blood test for assessing plasma TSH, T4, T3, FT4, TBG and Tg.

•• Urine collection for assessing urinary iodine excretion (UIE), and urinary iodopeptides

excretionn or LOMWIOM (low molecular weight iodmated material). This can be especially

helpfull in diagnosing the dyshormonogenesis: Tg synthesis defect.

•• Imaging studies of the thyroid gland. Sometimes an expert thyroid ultrasound will be

sufficient,, however, often a '23l uptake study (see III. 1.2) is needed to distinguish between

thee different forms of thyroid dyshormonogenesis and to localize a dysgenetic remnant.

Afterr the initial results are known, additional investigations such as molecular biologic

(genetic)) studies or pituitary function tests are sometimes needed. Table 3 is useful for the

interpretationn of certain plasma thyroid determinants.

111-11 _ Imaging studies in CH.

Figur ee 15: Ultrasound image showing a symmetrical,, enlarged thyroid gland, not detectedd by physical examination in a patient withh the thyroid dyshormonogenesis: TIOD.

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111.1.1.. Thyroi d Ultrasoun d Studies .

Performingg a reliable thyroid ultrasound study in newborns is a complicated procedure and

requiress extensive experience and patience. In the Emma Children's Hospital AMC the

interpretationn of ultrasound images is a joint effort of both a radiologist and a pediatric

endocrinologist.. Figure 1 5 shows the ultrasound image of a patient with the dyshormono-

genesis:: TIOD. The advantages of ultrasound studies are:

•• The procedure is generally rapid.

•• The procedure is not invasive.

•• The patient receives no irradiation.

•• The results are directly available.

•• The necessary equipment is usually immediately available.

Disadvantagess are:

•• The procedure is sometimes hard to perform (in the case of a crying child).

•• The results can be hard to interpret and are not always conclusive.

•• No insight is acquired into the dynamics of the thyroid gland.

111.1.2.. Thyroida l Radioiodid e Uptak e (123l uptake) .

Thee thyroid's ability to accumulate I via NiS provides the basis for diagnostic imaging with

radioisotopes.. The administration of ' " I (preferably in the neonatal period) provides an

importantt way to gain insight into the dynamics of the pathological thyroid gland in CH.

Usually,, neonates received 1 MBq 123l intravenously, followed by measurements of the

uptakee above the thyroid every 30 minutes, over a period of at least two hours (an example

iss given in Figure 16). The radioiodine accumulated by the thyroid gland is measured using

aa gamma camera with a pinhole collimator. Correction for the amount of isotope circulating

MRU,, 1 WEEK OLD

^^ * < > <*

T=55 T=15 T=3@ T=60

T=900 T=128 T=130 T=135

T T

+PERCHL0RRTE E

Figur ee 16: Radioiodide mages of the thyroid of a neonatee with a TIOD, showing rapid uptake and rapidd release after sodium perchlorate administration. .

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inn the blood of the neck region, which is calculated by subtracting counts obtained over

anotherr region of the body, is of particular importance during the early periods following

'23ff administration. The percentage of thyroidal radioactive iodide uptake is calculated

fromm the counts that are accumulated per constant time unit, i.e. 5 minutes in our setting.

Furtherr technical details are available in the Appendix.

Figur ee 17: Plot of serial measurements of thyroid 123l uptake after intravenous administration of l23t (0.99 MBq) and then, at 125 minutes, administration of sodium perchlorate (100 mg, intravenously). Thee ,23 lwas taken up more rapidly than normal, and then some was released. Blocking uptake with sodiumm perchlorate resulted in immediate release of ' 2 3 l , indicating that it was non-oxidized and non-organifiedd iodide. The release of all ,23l within 30 minutes after sodium perchlorate administration indicatess the complete inability of the patient's thyroid to oxidize and organify iodide, indicating the patientt has a TIOD.

PerchloratePerchlorate Discharge Test.

Thee perchlorate discharge test is used to detect defects in intrathyroidal iodide organification

andd is based on the following principle. After iodide is "trapped" by the thyroid gland

throughh an energy-requiring active transport mechanism (NIS), the trace element is rapidly

boundd to Tg preventing immediate efflux by diffusion. Several anions, such as thiocyanate

(SCN)) and perchlorate (CIOJ, inhibit active iodide influx and cause the release of the

intrathyroidall iodide not bound to protein. Thus, measurement of intrathyroidal radioiodine

losss following the administration of an inhibitor of iodide trapping would indicate the

presencee of an iodide-oxidation/binding defect. In the 123l uptake study, epithyroid counts

aree obtained at frequent intervals of 30 minutes following the administration of radioiodide.

Wee administer 100 mg NaCIOd intravenously at 125 minutes (40). After sodiumperchlorate

iss administered, the release of accumulated iodine is measured by repeated epithyroid

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countss at least every 15 minutes for one hour. Figure 17 exemplifies the plot of an ";3I

uptakee study with the administration of NaCI04.

Thee administration of an iodide transport inhibitor (e.g. sodiumperchlorate) creates an

instantaneouss inhibition of the active 123l influx. This influx is under normal circumstances

inn balance with the passive efflux of 1 2 3 l . Through this intervention a situation is created in

whichh the efflux of non-organified iodide becomes immediately evident. A release (efflux)

greaterr than 20% percent indicates an organification defect (40). The perchlorate discharge

testt is also positive in another inborn error of iodide organification, the PIOD or the

combinationn of PIOD with sensorineural hearing loss (Pendred's Syndrome).

IV.. Treatmen t / thyroxin e supplementatio n in CH.

Ourr most important recommendations for treating CH are:

1.. Begin T4 supplementation as early as possible.

2.. A state of euthyroidism needs to be reached as soon as possible.

3.. During the first few weeks of T4 supplementation frequent controls of certain thyroid

determinants,, especially plasma FT4, are necessary to prevent over- or undertreatment.

IV.1.. T4 Supplementation . Ann initial daily T4 dosage of around 10 (ig.kg1 is usually sufficient. The supplementation

dosagee of T4 is dependent on body mass, age, and intestinal resorption, and less on CH

etiologyy or severity (179). In practice, some pediatricians tend to give higher dosages to

neonatess who suffer from more severe forms of CH (personal observation). Recent follow-

upp data on Dutch CH patients whose mental and psychomotor development was assessed

beforee the age of 3 years, show that higher T4 supplementation dosages (i.e. daily T4 >

9.55 ng.kg') gave (supra)normal results in the development tests (14). Chapter 3 discusses

thiss in more detail.

Certainn alimentary substances (such as soy products) or intestinal problems can hinder the

intestinall resorption of T4. In our research, one infant had to be excluded from the study

groupp described in Chapter 3 because a soy formula was introduced during T4

supplementation.. After the introduction of soy formula, plasma TSH increased while plasma

FT44 levels rather abruptly decreased.

Inn the early years of screening for CH in The Netherlands (early 1980s) T3 was administered

priorr to administration of T4, but a few years later it was replaced by T4 supplementation

alonee because of new insight into the function of (cerebral) iodothyronme deiodinases.

lodothyroninee deiodinase type II was (and still is) considered to be responsible for the major

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CC hapteH

sourcee of T3 in the brain (converted from plasma T4). More recently, there is research discussing

thee brain protective effect of T3 in the treatment of acquired hypothyroidism in adults (18).

Thiss new finding in adults requires our attention in the treatment of children with CH.

IV.2.. Euthyroidism . Euthyroidismm is our goal during the treatment of CH. Defining the condition, however,

dependss on certain circumstances. For example, with respect to plasma FT4 normalization

inn the early phase of treatment, the severity of CH needs to be considered in (re)assessing

thee target range for FT4. The central issue is cerebral euthyroidism, which is probably not

presentt until plasma TSH has normalized. In the treatment of CH, TSH normalization is

usuallyy the case after approximately 5 weeks of T4 supplementation, see Chapter 3.

V.. Some geneti c aspect s of CH.

Ass in other genomes, the DNA of the human genome is not a static entity. Instead, it is

subjectt to different types of heritable change (mutation). Large-scale chromosome

abnormalitiess involve loss or gain of chromosomes or breakage and rejoining of chromatids.

Smallerr scale mutations can be grouped into different mutation classes and can also be

categorizedd on the basis of whether they involve a single DNA sequence (simple mutations)

orr whether they involve exchanges between two allelic or nonallelic sequences. Three

classess of small-scale mutation can be distinguished (160):

1.. Base substitutions involve replacement of usually a single base; in rare cases several

clusteredd bases may be replaced simultaneously as a result of a form of gene conversion.

2.. Deletions involve one or more nucleotides that are eliminated from a sequence.

3.. Insertions involve one or more nucleotides that are inserted into a sequence; in rare

casess transposition from another locus is involved.

Forr an overview of the incidence of mutation classes in the human genome, see Table 5. In

Chapterss 4, 5, and 6, mutations in the TPO gene and the POU1F1 gene are discussed in

relationshipp to CH. The first type of mutations defines thyroidal CH and the second type

leadss to pituitary CH. Mutations discussed in these chapters can be defined as follows:

•• Frameshift mutation: a mutation that alters the normal translational reading frame of a

mRNAA by adding or deleting a number of bases that is not a multiple of three; often

resultingg in a termination signal.

•• Missense mutation: a nucleotide substitution that results in an amino acid change.

•• Nonsense mutation: a mutation that occurs within a codon and changes it to a stop codon.

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Mutationn class

Basee substitutions

Chromosomal l

abnormalities s

Typee o ' mutation

Alll types

Transitionss and

transversions s Synonymouss and

nonsynonyrnous s substitutions s

Genee conversion-liKe eventss fmuitiple base substitution) )

Off one or a tew.

nucleotides s Triplett repeat

expansions s Otherr large insertions

Off one or a few nucleotides s

Largerr deletions

Numericall and

structural l

incioence e

Comparativelyy common type of mutation in coding DNA but also common in

noncodmgg DNA

Unexpectedlyy transitions are commoner man transversions. especially in

mitochondriall DNA

Synonymouss substitutions are considerably more common than

nonsynonyrnouss suDst tut,ons in coding DNA conservative Substitutions are

moree common than nonconservative

Raree except at certain tandemiy repeated loci or clustered repeats

Veryy common in noncodmg DNA but rare in coding DNA where they produce

frameshifts s

Raree but can contribute to several disorders especially neurological disorders

(seee Box 16 7\

Rare:: can occasionally get large scale tandem duplications, and also insertions

off t ransposable elements (Section 9 5 6i

Veryy common in noncodmg DNA but rare in codmu DNA where they produce

frameshifts s

Raree but often occur at regions containing tandem repeats (Section 9 5 3) or

betweenn interspersed repeats Isee Section 9.5.4 and Figure 9.9)

Raree as constitutional nu ta t ions , but can often be pathogenic isee Section 2 6i.

Muchh more common as somatic mutat.ons and often found m tumor cells

Tablee 5: Incidence of mutation classes in the human genome (From Strachan T & Read AP. Human molecularr genetics 2, 1999, p 209, with permission from BIOS Scientific Publishers Ltd., Oxford, UK).

Inn Chapter 5 the concepts genomic imprinting and uniparental disomy (UPD) are used, the

followingg definitions are useful:

•• Genomi c imprinting : the determination of the expression of a gene by its parental origin.

Thee mechanism of genomic imprinting is unclear but a key component appears to be the

DNAA methylation pattern (160). Genomic imprinting plays an important role in human

development,, its deregulation can cause certain defined disease states (100). Well-known

exampless in the pediatric practice are Prader-Willi (lack of paternal genes at chromosome

11 5q 11 -q 13) and Angelman syndromes (lack of maternal genes at 15q 11-q13).

•• Uniparenta l Disom y (UPD) represents an imbalance in the distribution of paternal and

maternall chromosomes in offspring. UPD is defined as the presence (in a diploid individual)

off two homologues of a specific chromosome pair inherited from only one parent

(54,55,99).. This condition can be complete or partial. Uniparental heterodisomy is the

conditionn where both chromosome homologues in the offspring originate from one

parent,, but are different from each other. If two identical copies of one single parental

homologuee are present, the condition is called uniparental isodisomy. The patient

describedd in Chapter 5 is an example of partial maternal isodisomy. Genomic imprinting

cann be a consequence of UPD (56,57,104).

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