François M. Delange
Many people with severe endemic goiter have irreversible impairment of intellectual and physical development. These abnormalities are extremely polymorphous and have been grouped under the general heading of endemic cretinism. The prevalence of the disorders may reach 5% to 15% of the population. It is by far the most serious complication of endemic goiter and represents a veritable scourge, both medically and socially (1,2,3).
Despite recent experimental data, the etiopathogenesis of endemic cretinism remains only partly understood (see later sections Etiology and Pathogenesis), and information on its pathology is scanty (4,5,6). For these reasons, the diagnosis of the condition is still mostly descriptive.
This chapter summarizes the present knowledge on the epidemiology and clinical manifestations, laboratory data, etiology, pathogenesis, therapy, and prevention of endemic cretinism. A comprehensive bibliography, including the historical aspects, is available in more extensive reviews on the topic (1,2,3,4,5,6,7,8,9,10,11).
EPIDEMIOLOGY, CLINICAL MANIFESTATIONS, AND LABORATORY DATA
In 1986, a study group of the Pan American Health Organization (PAHO) formulated the following definition of endemic cretinism (12):
The condition of endemic cretinism is defined by three major features:
A. Epidemiology. It is associated with endemic goiter and severe iodine deficiency.
B. Clinical manifestations. These comprise mental deficiency, together with either:
1. A predominant neurological syndrome including defects of hearing and speech and characteristic disorders of stance and gait of varying degree; or
2. Predominant hypothyroidism and stunted growth. Although in some regions, one of the two types may predominate, in other areas a mixture of the two syndromes will occur.
C. Prevention. In areas where adequate correction of iodine deficiency has been achieved, endemic cretinism has been prevented.
The clinical manifestations of endemic cretinism summarized in the PAHO definition correspond to the two extreme types of endemic cretinism initially defined in the pioneering work of McCarrison in 1908 (13) in the Himalayas and subsequently reported in the studies of endemic goiter and cretinism conducted in other parts of the world, for example, New Guinea (14,15) and the Democratic Republic of Congo (DRC, formerly Zaire) (16,17,18,19,20,21,22,23). The first type is marked by neurologic disorders (neurologic cretinism) and the second by symptoms of severe thyroid insufficiency (myxedematous cretinism).
Figure 49.1 shows the typical picture of neurologic cretinism as seen in New Guinea (14,15): the cretins in this endemia are extremely mentally retarded, and most of them are reduced to a vegetative existence. Almost all are deaf-mutes and have the following neurologic defects: (a) impaired voluntary motor activity, usually involving the pyramidal track, chiefly affecting the lower limbs, with hypertonia, clonus, and plantar cutaneous reflexes in extension—extrapyramidal signs are occasional; (b) spastic or ataxic gait—in the severest cases, walking or even standing is impossible; and (c) strabismus.
FIGURE 49.1. A 14-year-old boy with neurologic endemic cretinism, Mulia Valley, Western New Guinea. The boy has severe mental retardation, deaf-mutism, spastic diplegia, and strabismus. There are no clinical signs of hypothyroidism. Serum protein bound iodine (PBI) 1.7 µg/dL. (Photograph courtesy of Professor A. Querido, Leiden, The Netherlands.)
The prevalence of goiter in these cretins is as high as in the noncretin population of the area, and they are clinically euthyroid. Thyroid function is usually normal (14,15), but subclinical hypothyroidism with high basal serum thyrotropin (TSH) or exaggerated TSH response to thyrotropin-releasing hormone (TRH) may occur (24,25).
Figure 49.2 shows the typical picture of myxedematous endemic cretinism as most typically seen in the DRC (3,7,16,17,18,19,20,21,22,23). These cretins have less mental retardation than the neurologic cretins; they are often capable of performing simple manual tasks. All have major symptoms of long-standing hypothyroidism: dwarfism, myxedema, dry skin, sparseness of hair and nails, retarded sexual development, and retarded maturation of body proportions and of naso-orbital configuration. The initial reports from the DRC indicated that myxedematous cretins occasionally had neurologic signs, including spasticity of the lower limbs, jerky movements, Babinski's sign, and shifting gait (18,23).
FIGURE 49.2. Myxedematous endemic cretinism in children in Ubangi, northwestern DRC. On the left, a clinically euthyroid 6-year-old girl with a height of 105 cm (50th percentile for age for the local population). On the right, a 17-year-old girl with a height of 100 cm, severe mental retardation, myxedema, markedly delayed puberty, flat and broad nose, hypoplastic mandibule, dry and scaly skin, dry and brittle hair, and prominent abdomen. Pseudomuscular hypertrophy, muscular weakness, flat feet, and genu valgum are present; no deaf-mutism. The thyroid gland was not palpable. Har serum concentration of thyrotropin was 288 µU/mL, thyroxine 0.1 µldl (1.29), and triiodothyronine 10 ngldl (0.154 nM).
The prevalence of goiter in the myxedematous cretins is much lower than in the noncretin population. Many have palpable thyroid tissue, although thyroid scintigrams show small amounts of thyroid tissue located in normal position (18,23), precluding thyroid dysgenesis (agenesis, ectopic thyroid) as the cause of hypothyroidism.
The clinical diagnosis of hypothyroidism in myxedematous cretins is confirmed by a biochemical picture of thyroid failure with almost undetectable serum concentrations of thyroxine (T4) and triiodothyronine (T3) and extremely elevated serum levels of TSH (Table 49.1). The iodine pool of the thyroid is drastically reduced with a particularly fast turnover rate of iodine, as indicated by elevated serum radiolabeled protein bound iodine (PB131I). The diagnosis of severe and long-standing hypothyroidism is further confirmed by a very important retardation in bone maturation and epiphyseal dysgenesis, indicating hypothyroidism of perinatal onset, and by characteristic changes in the electrocardiogram (23).
TABLE 49.1. THYROID FUNCTION TESTS AND CLINICAL AND RADIOLOGIC DATA IN HYPOTHYROID ENDEMIC CRETINS IN DRC, CHINA, AND INDONESIA
Hypothyroid Endemic Cretins
(n = 12–255)
Noncretin Iodine-Deficient Adults (DRC)
(n = 30–358)
(n = 6–120)
(n = 25)
(n = 3)
Thyroid function tests
Serum concentration of
104.2 ± 1.3
63.1 ± 2.6
6.4 ± 0.1
53.9 ± 7.1
8.4 ± 1.3
2.21 ± 0.05
2.55 ± 0.04
0.70 ± 0.05
2.1 ± 0.2
1.7 ± 0.1
18.6 ± 2.1
303 ± 20
123.8 ± 23.0
Protein bound 131I (% dose/liter)
0.06 ± 0.01
0.17 ± 0.02
1.09 ± 0.18
24-hour 131I thyroid uptake (% dose)
46.4 ± 1.1
65.2 ± 0.9
28.3 ± 2.6
Thyroid organic iodine pool (mg)
15.8 ± 3.5
1.60 ± 0.3
Clinical and radiologic data
Clinical myxedema (%)
Bone maturation (yr)
Mental development vs. euthyroid cretins
DRC, Democratic Republic of Congo
Values recorded as mean ± SEM.
Data from references 18, 20, 44, 48, 114, 116, and 125.
The review of the world literature on endemic cretinism up to the late 1970s indicated that the frequency distribution of the two extreme types of endemic cretinism varied markedly from one endemic area to another. In most of them, the neurologic type predominated, while in others, especially in DRC, myxedematous endemic cretinism was most frequently encountered. The reasons for these geographical variations in the epidemiologic pattern of endemic cretinism were unknown. It was also agreed that, between the two extreme types of cretinism, there were mixed forms characterized by dominant neurologic disorders or dominant hypothyroidism in the same individual (8,14,15,16,17,18,19,20,21,22,23,26,27,28,29,30,31,32,33,34,35,36).
It was then thought that neurologic and myxedematous endemic cretinism, in fact, constituted the extreme aspects of a continuous spectrum of developmental abnormalities, between which there were numerous intermediate forms (7,8,37). A similar variability in the geographic pattern of endemic cretinism has been reported from China: neurologic cretinism has been found in almost all the cretin endemias of China; the myxedematous type was less frequent and was found principally in the northwestern part of the country (38,39,40).
The results of subsequent detailed studies of cretinism in Ecuador (41,42,43), China (44,45,46,47), Indonesia (48), and Thailand (49,50) vigorously challenged the concept of a continuous spectrum of developmental abnormalities in endemic cretinism between two extreme types, myxedematous and neurologic. The main reason is that in their studies in China and Indonesia, the Australian researchers reported an identical pattern of intensity of neurologic, intellectual, and audiometric deficits in all cretins examined, regardless of type (myxedematous or neurologic) and current thyroid function (44,48). The neurologic aspects of both euthyroid and hypothyroid cretins are polymorphous and vary widely from one subject to another: in the 139 subjects they investigated in China and Indonesia, Halpern and colleagues (48) reported significant pyramidal dysfunction in a proximal distribution and exaggeration of the tendon reflexes, more commonly encountered in the lower limbs than in the upper. The posture is typical, with hips and knees flexed and the trunk tilted forward. The gait is broad based and knock-kneed. The arms are held with the shoulders abducted and the elbows flexed. These signs indicate extrapyramidal features. All the cretins have severe intellectual impairment, with a mean IQ of about 29. About half the patients have impaired hearing, and nearly one third have a squint. Musculoskeletal abnormalities are common and predominantly involve the weight-bearing joints, with excessive laxity of the hips, feet, and ankles. There are no signs of cerebellar dysfunction.
Subsequently, Rajatanavin and colleagues (49) reported a similar frequency of low intelligence, defects in visual perceptive neuromanual ability, sensorineural hearing loss, and neurologic defects in 57 neurologic, 19 myxedematous, and 36 mixed cretins in northern Thailand.
In another study conducted in China, in an attempt to better define the underlying pathology in the nervous system causing the functional deficits and to determine the developmental timing of the critical neurologic events, Delong and colleagues (47) identified five patterns of neurologic involvement in these cretins:
1. “Typical” pattern, with hearing and speech deficit, proximal spastic rigid motor disorder, and mental retardation
2. “Thalamic” posturing, with undermost limbs extended and uppermost limbs flexed, together with severe mental retardation, marked microcephaly, inability to sit, stand, or walk, and primitive facial reflexes including a marked sucking or rooting reflex elicited by bringing an object into the visual field near the face
3. An autistic pattern, with severe mental deficiency aggravated by deaf-mutism and an almost total disregard of their surroundings and absence of purposeful activity
4. A cerebellar pattern, with marked abnormalities in standing, walking, and sitting, hypotonic truncal tone, tremor, and dysmetria that are typical of cerebellar dysfunction
5. A hypotonic pattern, with marked truncal hypotonia and delayed sitting, standing, and walking
The hypothesis was proposed that the typical pattern may represent an insult occurring principally during the second trimester of pregnancy; that the severe thalamic form may represent a longer period of insult; that deafness results from a cochlear lesion occurring during the first and second trimesters; that the cerebellar form may result from a postnatal insult; and that the autistic form may depend on a severe insult to the cerebral cortex as well as the hippocampus, both pre- and postnatally (47,51).
In contrast to the exhaustive clinical descriptions of the nervous system defects in cretins and the diversity and severity of these deficits, information on brain pathology is scanty and does not elucidate entirely the anatomic locations of the injury: computed tomographic (CT) scans of cretins from Ecuador showed widespread atrophy that included the cerebral cortex and subcortical structures of the brainstem, with corresponding enlargement of the basal cisternae, the lateral ventricles, and the sulci over the surface of the cerebral cortex (52). Basal ganglia calcifications and cerebral atrophy were occasionally observed by Halpern et al (48), but there was no correlation between the CT scan abnormalities and the clinical signs. Magnetic resonance imaging in three cretins from China appeared remarkably normal (47).
On the basis of the observations in China, Indonesia, and Thailand, the concept was proposed that all cretins, including the so-called myxedematous form, belong to the neurologic type (44,48,50). The reason for the discrepancy between this concept and the concept of a spectrum with two extreme types is unclear. One possible explanation could be an underevaluation or misinterpretation of the neurologic signs in myxedematous cretins in DRC by the different Belgian and African teams (43) which investigated the Uele, Idjwi Island, and Ubangi areas during the past 40 years (16,17,18,19,20,21,22,23). If so, the same mistakes were also made by the team from Washington, which again investigated the Uele area and obtained exactly the same epidemiologic findings (53). It has to be recognized that at least some of the neurologic signs found in the myxedematous cretins of the DRC, including flat feet, knock knees, hyperreflexia, ataxia, strabismus, nystagmus, and hearing defects, have been occasionally reported in the past in unrecognized and consequently untreated children with sporadic congenital hypothyroidism (54,55).
Another possible explanation of the difference between the two concepts could be that the term “myxedematous cretinism” has been applied in China and Indonesia to patients with predominantly neurologic cretinism and postnatally acquired hypothyroidism with moderate biochemical impairment of thyroid function, similar to that found in neurologic cretinism in other parts of the world and in noncretin, severely iodine-deficient adults (Table 49.1). In fact, the degree of hypothyroidism reported in the hypothyroid cretins in China and Indonesia is much milder than the hypothyroidism observed in Africa. The difference in severity is reflected by the results obtained for the biochemical tests and could explain why the retardation in height and especially in bone maturation is much less marked in hypothyroid cretins in China than in the DRC, where hypothyroidism is of perinatal onset. Only half of the myxedematous cretins in China are clinically myxedematous, while, by definition, all of them are in DRC.
The most probable explanation for the discrepancy between the two concepts, however, is that, although severe iodine deficiency is the main cause of all types of cretinism, additional causes, varying from place to place, may modulate the clinical expression of the disorder (see later sections Etiology and Pathogenesis).
ENDEMIC MENTAL RETARDATION IN SEVERE ENDEMIC GOITER
The statement that “feeble mindedness, a part of cretinism, arises distinctly in areas of endemic goiter” (56) has been rather difficult to confirm on an objective basis, particularly because of major technical limitations in the assessment of intelligence in preindustrialized societies (6,57).
Table 49.2 summarizes data available in the literature on the neuromotor and intellectual development in noncretinous people in areas with severe endemic goiter and cretinism. The same tests (optimally with no “cultural bias” or as little as possible) were administered to two groups of noncretinous subjects living in the same environmental conditions except for the goitrogenic factors: a test group was exposed to these factors, while in a control group, exposure was prevented by iodine prophylaxis, or these factors had never been present. In the test groups, neuromotor and intellectual deficits were frequently observed in subjects who did not have any of the other signs of endemic cretinism.
TABLE 49.2. INTELLECTUAL, COGNITIVE, AND NEUROLOGIC DEFICITS IN NONCRETINS IN SEVERE ENDEMIC GOITER REGIONS
Low DQ, IQ, and visual-motor performances
Low IQ and visual-motor performances
Low motor skill
Locally adapted “culture-free” intelligence tests
Low perceptual and neuromotor abilities
Low IQ—Relationship between IQ and nerve deafness and abnormal neurologic signs
Verbal, pictorial learning tasks
Test of motivation
Low rates of hearing
Thus, endemic cretinism only constitutes the extreme expression of a spectrum of abnormalities in physical and intellectual development and in the functional capacities of the thyroid gland in the inhabitants of severe endemic goiter areas.
Iodine deficiency is fundamental in the etiology of endemic cretinism. This conclusion rests on (a) the correlation between the degree of iodine deficiency and the frequency of cretinism (3,8,11); (b) the prophylactic action of iodine on the incidence of cretinism (see later section Prevention); and (c) the emergence of cretinism in previously unaffected populations as a consequence of iodine deficiency of recent onset, as observed in the Jimi valley in New Guinea after replacement of natural rock salt rich in iodine with low-iodine industrial salt (58) (see section Iodine Deficiency in Chapter 11).
In addition, iodine deficiency during gestation in animals results in thyroid deficiency in the offspring. All the models used mimic the myxedematous type of cretinism; none was able to reproduce the neurologic type (59,60,61).
Naturally Occurring Goitrogens
The additional role played by naturally occurring goitrogens in the etiology of endemic cretinism has been established for a cyanogenic glucoside (linamarin) present in cassava, a staple food in many tropical areas (19,20). Linamarin yields cyanide on hydrolysis. This is metabolized to thiocyanate (SCN), which is well known for its goitrogenic effects. The role of SCN in the etiology of endemic cretinism in Africa has been proposed from the observation that people in areas with severe but uniform iodine deficiency had cretinism only when a certain critical threshold in the dietary intake of SCN is reached (62). It has been shown experimentally in the rat that SCN affects the development of the central nervous system during fetal life (20). The action of SCN is entirely due to an aggravation of iodine deficiency resulting in fetal hypothyroidism.
Boyages and colleagues (63) reported that purified immunoglobulin G (IgG) fractions of serum from patients with myxedematous endemic cretinism inhibited TSH-induced DNA synthesis and, consequently, growth of guinea pig thyroid segments in a sensitive cytochemical assay. By contrast, no growth-blocking effect was observed with IgGs from euthyroid subjects or neurologic cretins from the same area. These IgGs, often called thyroid growth-blocking immunoglobulins (TGBIs), are similar to those found by the same researchers in sporadic congenital hypothyroidism (64). The antigenic stimulus is unknown, as is the timing of appearance of these IgG fractions during pregnancy and fetal or postnatal life. Serum TGBIs were also detected using rat thyroid FRTL-5 cells in cretins in Brazil with atrophic thyroids (65). However, TGBI could not be found in sporadic congenital hypothyroidism or myxedematous endemic cretinism in Peru and Italy by other researchers (66,67,68); consequently, the possible role of thyroid autoimmunity in the etiology of endemic cretinism remains controversial.
One question about the etiology of both myxedematous and neurologic endemic cretinism concerns the role of combined iodine and selenium deficiencies (69,70,71,72,73). In the DRC, myxedematous cretinism is found only in severe iodine-deficient areas that are also deficient in selenium (69,73) (Table 49.3). Selenium is present in high concentrations (0.72 µg/g) in the normal thyroid (74). It is present in glutathione peroxidase (GPX) and superoxide dismutase, the enzymes of the thyroid responsible for the detoxification of toxic derivates of oxygen (H2O2 and perhaps O2-) (75). It is also present in both iodothyronine 5′-deiodinases responsible for the conversion of T4 to T3 (76).
TABLE 49.3. COMPARISON BETWEEN AN AREA WITH SEVERE DEFICIENCIES IN IODINE AND SELENIUM AND OVERLOAD IN THIOCYANATE (UBANGI, NORTHERN DRC) AND CONTROL OF AREAS (BRUSSELS OR KIKWIT, DRC)
(n = 38–204)
(n = 140–243)
Prevalence of goiter (%)
Prevalence of cretinism (%)
Urinary concentration of
5.3 ± 0.7
2.3 ± 0.1
0.60 ± 0.07
1.82 ± 0.10
Serum concentration of
201.9 ± 5.23
27.1 ± 1.9
RBC-GPX (U/g Hb)
15.0 ± 0.8
3.3 ± 0.3
Cord serum concentration of
8.2 ± 0.4
70.7 ± 13.1
146.7 ± 2.6
95.2 ± 5.1
0.57 ± 0.01
1.47 ± 0.10
Epidemiologic data, variables exploring the nutritional status in iodine, SCN, and selenium (including RBC-GPX) and variables exploring thyroid function in cord blood. Values recorded as mean ± SEM. All the differences between the two groups are highly significant (p < .01 to p < .001).
RBC-GPX, red blood cell–glutathione peroxidase; SCN, thiocyanate; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.
Data from references 69, 71, and 99.
The following scheme has been proposed to explain the frequency of myxedematous cretinism and the relative rarity of neurologic cretinism in areas such as the DRC where both iodine and selenium are deficient (69,70,71,72) (Fig. 49.3): iodine deficiency results in hyperstimulation of the thyroid by TSH and consequently in increased production of H2O2 within the cells. Selenium deficiency results in GPX deficiency and consequently in accumulation of H2O2. Excess H2O2 could induce thyroid cell destruction and thyroid fibrosis, resulting in myxedematous cretinism. The recent observation that the necrotizing effect of a high dose of iodide on the thyroid cells is much greater in selenium-deficient than in selenium-supplemented rats is consistent with this hypothesis, suggesting that the selenium-deficient thyroid gland is more sensitive to oxidative stress (77). The necrotizing effect is aggravated in the presence of SCN overload (78).
FIGURE 49.3. Effects of selenium deficiency on thyroid function and thyroxine metabolism in the presence of severe iodine deficiency. GPX, glutathione peroxidase. (From Contempré B, Many MC, Vanderpas J et al. Interaction between two trace elements: selenium and iodine. Implications of both deficiencies. In: Stanbury JB, ed. The damaged brain and iodine deficiency. New York: Cognizant Communication, 1994:133, with permission.)
On the other hand, in pregnant women deficiency of the selenoenzyme iodothyronine 5′-deiodinase induced by selenium deficiency causes decreased catabolism of T4 to T3 and thus increased availability of maternal T4 for the fetus and its brain. Indeed, despite a similar degree of iodine deficiency, serum T4levels are higher in selenium-deficient pregnant women in the DRC than in pregnant women in New Guinea (51). This mechanism could prevent the development of neurologic cretinism. Combined iodine and selenium deficiencies together with SCN overload due to the chronic consumption of cassava could thus explain the large predominance of the myxedematous type of endemic cretinism, rather than the neurologic type, in the DRC.
Endemic cretinism results from an insufficient supply of thyroid hormone to the developing brain. The physiologic role of thyroid hormones is to ensure the timed coordination of different developmental events through specific effects on the rate of cell differentiation and gene expression (79). Thyroid hormone action is exerted through the binding of T3 to nuclear receptors, which regulate the expression of specific genes in different brain regions following a precise development schedule (79). During the fetal and early postnatal life, T3 bound to nuclear receptors is entirely dependent on its local production from T4 via type 2 deiodinase (D2) (80) (see Chapter 74).
Maternal and Fetal Hypothyroxinemia before Onset of Fetal Thyroid Function
Despite the independence of maternal and fetal hypothalamus–pituitary–thyroid feedback mechanisms (81), maternal thyroid hormone is involved in the development and thyroid hormone economy of the fetus.
In rats, thyroid hormones are found in embryonic and fetal tissues before the onset of fetal thyroid function, which occurs at day 18 (82). The hormones are thus of maternal origin. Their concentrations remain fairly constant until day 18, when the fetal thyroid secretion begins (83). After day 18, the fetal thyroidal T4 and T3 pools as well as the circulating T4 level increase steadily (84). At term, 17.5% of the fetal extrathyroidal T4 is still of maternal origin (85).
In iodine deficiency, the rat embryo is T4 deficient, and its brain is exposed to variable T3 deficiency not only because of its own impairment of T4 synthesis but also, and perhaps predominantly, because of maternal hypothyroxinemia and insufficient transfer of T4 from mother to fetus in early pregnancy, before the onset of fetal thyroid activity (86).
The key role of maternal T4 during early gestation on the brain development of the fetus is demonstrated by the observation that in the 40-day-old progeny of hypothyroxinemic iodine-deficient pregnant rats, there is a significant proportion of neurons that are aberrant or inappropriate locators with respect to their birthdate (87). This is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that can be only related to early maternal hypothyroxinemia.
An additional cause of fetal hypothyroxinemia in iodine deficiency is that the fetal thyroid, contrasting with the maternal thyroid, is unable to increase its avidity for iodide, that is, its iodide clearance rate in case of decreased serum concentration of iodide (88), despite up-regulation of Na+/I- symporter expression in fetal thyroid and placenta during iodine deficiency (89). This will further decrease the iodine stores of the fetal thyroid and, consequently, T4synthesis.
A partial mechanism of adaptation to fetal hypothyroxinemia in rats is that, in these circumstances, there is an increase in fetal brain deiodinase type 2 activity that protects the fetal brain from T3 deficiency, even when euthyroidism is not maintained in other fetal tissues (90). In contrast, the transfer of maternal T3 does not protect the hypothyroid fetal brain from T3 deficiency.
In humans, T4 is present in coelomic fluid 6 weeks of gestational age (91). Nuclear T3 receptors are present in the brain of 10-week-old fetuses, and increase more than sixfold by 12 weeks and tenfold by 16 weeks (92), largely before the onset of fetal thyroid function, which occurs by 14 weeks of gestation. However, evaluation of fetal tissue exposure to maternal thyroid hormones up to midgestation indicated that first-trimester human fetal tissues are exposed to concentrations of T4 of at least one third of those in their euthyroid mothers (93). These findings further underline the critical role of maternal thyroxinemia on the timely sequence of brain development in the human fetus. Fetal plasma T4 is low although detectable up to the 14th week of gestation. After the onset of fetal thyroid function, T4 increases steadily, reaching adult values by 36 weeks (94). However, transfer of maternal T4 continues until birth, when it still represents 20% to 50% of cord serum T4 (95).
Maternal hypothyroxinemia is rare in nonendemic areas, but it can result in impaired neurointellectual development in the offspring (5,96,97,98). In contrast, maternal hypothyroxinemia is extremely frequent in endemic areas (99,100). It is associated with increased mortality and morbidity in offspring (101,102), and increased incidence of hypothyroidism in neonates (99,103).
A unifying concept has been proposed that the neurologic defects, present in all cretins, are due to maternal and fetal hypothyroxinemia (48,50). This would account for the picture of cretinism as found in China and Indonesia. In Africa, as indicated earlier, brain damage during early fetal life could be mitigated by concomitant selenium deficiency, which impairs peripheral conversion of T4 to T3 and consequently increases the availability of the prohormone T4 to the fetal brain.
Fetal and Neonatal Hypothyroidism after Onset of Fetal Thyroid Function
Even a moderate degree of iodine deficiency during pregnancy, as occurs in Western Europe, can be accompanied by indexes of hyperstimulation of the thyroid in the neonates, as indicated by high serum levels of TSH and thyroglobulin (Tg) and by a slight enlargement of the thyroid. These abnormalities are prevented by the daily administration of a physiologic dose of iodide to pregnant women throughout pregnancy (104).
As noted above, the myxedematous endemic cretinism results from severe thyroid failure occurring during late fetal or early postnatal life: data from China have shown hypothyroxinemia and retardation in brain growth in human fetuses from the sixth month of gestation in regions of severe iodine deficiency and myxedematous endemic cretinism (105). Thyroid failure at birth due to iodine deficiency occurs in several endemic areas with myxedematous endemic cretinism, such as the DRC (99,103), India (106), Algeria (107), and even some parts of Europe such as Sicily (108). The most dramatic picture of neonatal hypothyroidism has been reported from DRC, where the frequency of myxedematous endemic cretinism is the highest: in this area, about 10% of unselected newborns and infants 1 to 24 months of age have both serum TSH above 100 µU/mL and T4 levels below 3.1 µg/dL (40 nM) (99,103), a biochemical picture characteristic of congenital hypothyroidism in Western countries (109,110). About 10% of infants under 12 months of age are clinically hypothyroid, and nearly half have a marked delay in bone maturation, which is directly correlated with serum TSH and inversely correlated with serum T4 (99,103). Finally, correction of iodine deficiency in pregnant women by injections of iodized oil results in a complete normalization of the biochemical and radiologic indexes of hypothyroidism in newborns and infants (103,111).
The presence of epiphyseal dysgenesis in x-ray studies of the knees (Fig. 49.4B) of some adult myxedematous endemic cretins with clinical, biochemical, and radiologic signs of long-standing hypothyroidism suggests that hypothyroidism was present before or around birth (112). Also, the direct correlations observed in these cretins between mental retardation and both height retardation and retardation in bone maturation indicate that hypothyroidism present in early life would account for their mental deficiency (17).
FIGURE 49.4. Clinical appearance (A) and knee x-ray (B) of a 17-year-old myxedematous cretin of Idjwi Island, DRC, with a height of 87.5 cm (56% of normal for the local population) and a serum protein bound iodine (PBI) of 1.0 µg/dL. Bone maturation is estimated at 2 to 5 years. The x-ray film shows failure of modeling, and tibial and femoral epiphyseal dysgenesis. The immaturity of the naso-orbital configuration, the mandibular hypoplasia, and the epiphyseal dysgenesis indicate hypothyroidism of pre- or perinatal onset.
In some infants in the Ubangi area in DRC, the biochemical signs of thyroid failure disappeared spontaneously within 6 to 10 weeks of life (113). The hypothesis has been proposed that permanent thyroid failure from birth results in myxedematous endemic cretinism, whereas transient hypothyroxinemia occurring during the critical period of brain development explains the endemic mental retardation in this population (114).
The cause of fetal hypothyroidism in the DRC is most likely the combined action of iodine deficiency and SCN overload. The latter results from the chronic consumption of cassava, which aggravates the effects of iodine deficiency (19,20). SCN freely crosses the placenta (115), and its concentration in cord blood is three times higher in Ubangi than in Brussels (99). The importance of this SCN overload in the impairment of thyroid function of the newborn is strongly suggested by the observation that, in severely iodine-deficient pregnant women, high urinary SCN values are associated with very high serum TSH and very low cord serum T4 levels (99). The hypersensitivity of the newborn to the antithyroid action of SCN probably results from the fact that this ion interferes with the trapping of iodide by both the placenta and the thyroid gland of the newborn. These two factors probably critically reduce the buildup of iodine stores within the thyroid gland during fetal and early postnatal life. This mechanism is consistent with the low iodine content of the thyroid gland reported in myxedematous cretins (116) (Table 49.1).
As discussed earlier, selenium deficiency could further aggravate thyroid failure during the late fetal and neonatal periods by damaging the hyperstimulated gland through the accumulation of H2O2 derivatives. This process, called exhaustion atrophy, would explain the usual absence of goiter in the myxedematous cretins in the DRC.
In addition, iodine deficiency can induce thyroid failure at any time, including after brain development, resulting in infantile hypothyroidism without the irreversible brain damage characteristic of cretinism (28,117,118).
This unifying view of the pathogenesis of endemic cretinism would account for the differences in the epidemiologic and clinical aspects of cretinism seen around the world. Iodine deficiency is a prerequisite. When present during early gestation before onset of fetal thyroid function, it would account for the neurologic aspects of cretinism via maternal and fetal hypothyroxinemia. Selenium deficiency could mitigate the neurologic picture by increasing the availability of the prohormone T4 to the developing brain. It also could induce irreversible damage of the thyroid. Severe iodine and selenium deficiencies aggravated by SCN overload present during late pregnancy, after the onset of active fetal thyroid function, would account for the myxedematous component of cretinism.
It thus appears that the particular situation reported in the DRC with less neurologic damage and severe thyroid failure could be explained by a combination of severe iodine and selenium deficiencies complicated by SCN overload. The consequences of these three conditions are prevented by the correction of iodine deficiency in the pregnant mother.
There is no specific therapy for neurologic endemic cretinism. These patients need rehabilitation as do patients with cerebral palsy in Western countries. Thyroid function may improve after iodine supplementation in myxedematous cretins under 4 years of age but not in older patients, suggesting that in this type of cretinism the atrophic thyroid progressively loses its functional capacity (119,120). Some researchers, however, have reported significant improvement in neuromotor and physical appearance even in 30- to 40-year-old myxedematous endemic cretins treated with injections of iodized oil (53).
Endemic cretinism is prevented when iodine deficiency has been corrected (3,5,8,11,111,121). Iodization of salt introduced independently in various Swiss cantons between 1922 and 1925 resulted in a decline in endemic deaf-mutism in these cantons that could be correlated with the extent of salt iodination (122). However, it must be pointed out that in Switzerland endemic cretinism started to diminish about 10 years before the introduction of iodine prophylaxis (5), probably because of improved socioeconomic conditions, resulting in a “silent iodine prophylaxis.”
Table 49.4 summarizes the results of the controlled trials conducted during the past 20 years on the effect of iodine prophylaxis on the incidence of endemic cretinism. In Ecuador, in an attempt to study the effectiveness of iodine supplementation in early fetal life, pregnant women in the test village (Tocachi) were given iodine supplementation. Mothers who were in the sixth, seventh, eighth, and ninth months of pregnancy at the time of iodization were excluded. There have been no new cases of endemic cretinism among the infants investigated in the treated village, whereas six instances of severe and persistent mental and neuromotor deficiencies have appeared in the control village (123). The data of Pharoah and colleagues (124) indicate that iodized oil injections prevent neurologic endemic cretinism in offspring only if administered before pregnancy, indicating that the damage occurs during early fetal life.
TABLE 49.4. PREVENTION OF ENDEMIC CRETINISM BY INJECTIONS OF IODIZED OIL
One village injected (Tocachi).
One village not injected (La Esperanza).
Follow-up of the children born in the two villages up to 60 mo of age.
No cretin among the 205 children born in the treated village.
Six neurologic cretins among the 447 children born in the untreated village.
Families injected or not injected at random. Follow-up of the children up to 60 mo of age.
Six neurologic cretins among the 687 children in the treated group; in five of the six, the mother was pregnant at the time of injection.
Thirty-one cretins among the 688 children in the untreated group.
Two villages injected. One village not injected. Surveys after 1, 3.5, and 5 yr in the treated villages and after 5 yr in the untreated village.
No cretin born in the treated villages. Three myxedematous cretins were born in the untreated village during the fifth year of the investigation.
Pregnant women injected at random between the 20th and 36th wk of gestation (mean 28th wk).
Follow-up of 99 infants age 1.5–15 mo (mean 6.5 mo).
One myxedematous cretin among 44 infants in the treated group (mother injected during the last month of gestation).
Four myxedematous cretins among 45 infants in the untreated group.
Follow-up of 671 infants and children age 0–7 yr.
In infants 0–2 yr, myxedematous cretinism in 1/192 in the treated group and 10/109 in the untreated group (p < .01). The difference disappeared in children 3–7 yr.
The data from DRC show that correction of iodine deficiency prevents myxedematous endemic cretinism in the offspring even if administered during pregnancy (103). Subsequent studies showed that correction of iodine deficiency in pregnant mothers does not protect the infants against hypothyroidism for more than 2 to 3 years (111). The possibility that in some children, hypothyroidism could start after the age of 3 years is consistent with the observation of Goslings and colleagues (28) that hypothyroid patients in severe endemic goiter are not necessarily affected by severe and irreversible mental retardation and of Boyages and colleagues (44) that cretins with thyroid failure may have only moderate retardation in height and bone maturation (Table 49.1).
The epidemiology, clinical manifestation, laboratory data, therapy, and prevention of endemic cretinism are presently well established. Its etiopathogenesis is much better understood. Iodine deficiency appears to be an essential factor and, if severe enough, may be the sole factor in its causation. Selenium deficiency, if present, is an additional factor that results, on the one hand, in a risk of thyroid damage during the perinatal period and, on the other hand, in an increased availability of the prohormone T4 of maternal origin to the fetal brain. Thiocyanate, if present, aggravates the effects of both iodine and selenium deficiencies, both in the mother and the fetus, as it freely crosses the placenta.
Distinction between the neurologic and myxedematous types of endemic cretinism is not required any longer for two reasons: (a) it is difficult to justify from an epidemiologic and clinical point of view, and (b) the various manifestations of cretinism are critically related to the degree, timing, and duration of the action of the different dietary goitrogenic factors, including iodine deficiency. The level of serum T4 of the mother during gestation and the transfer of maternal T4 to the fetus and neonate, especially during early gestation even before the onset of fetal thyroid function, are the determining factors in the occurrence of irreversible brain damage. The second trimester appears as the period of maximum vulnerability of the brain. Maternal hypothyroxinemia appears as the determining factor in the pathogenesis of the neurologic picture and selenium deficiency in the thyroid damage and failure in endemic cretinism, respectively. The respective importance of these two factors depends on the local goitrogenic factors in the diet.
Because of the gravity of the condition and the well-established preventive action of iodine, an efficient iodine prophylaxis is urgently needed in areas affected by endemic goiter and cretinism.
1. Stanbury JB, Ermans AM, Hetzel BS, et al. Endemic goitre and cretinism: public health significance and prevention. WHO Chron 1974;28:220.
2. Hetzel BS, Dunn JT, Stanbury JB. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier, 1987.
3. Delange F. Endemic cretinism. An overview. In: Delong GR, Robbins J, Condliffe, eds. Iodine and the brain. New York: Plenum, 1989:219.
4. De Quervain F, Wegelin C. Der Endemische Kretinismus. Berlin: Springer Verlag, 1936.
5. König MP. Die Kongenitale Hypothyreose und der Endemische Kretinismus. Berlin: Springer Verlag, 1968.
6. Stanbury JB. The damaged brain of iodine deficiency. New York: Cognizant Communication, 1994:1–335.
7. Dumont JE, Delange F, Ermans AM. Endemic cretinism. In: Stanbury JB, ed. Endemic goiter. Washington, DC: Pan American Health Organization (publication no. 193), 1969:91.
8. Pharoah P, Delange F, Fierro-Benitez R, et al. Endemic cretinism. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism: iodine nutrition in health and disease. New York: John Wiley, 1980:395.
9. Hetzel BS, Querido A. Iodine deficiency, thyroid function, and brain development. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley & Sons, 1980:461.
10. Hetzel BS. The story of iodine deficiency. Oxford, UK: Oxford University Press, 1989.
11. Querido A. History of iodine prophylaxis with regard to cretinism and deaf-mutism. In: Stanbury JB, Kroc RL, eds. Human development and the thyroid gland: relation to endemic cretinism. New York: Plenum, 1972:191.
12. Delange F, Bastani S, Benmiloud M, et al. Definitions of endemic goiter and cretinism, classification of goiter size and severity of endemias, and survey techniques. In: Dunn JT, Pretell E, Daza CH, et al., eds. Towards the eradication of endemic goiter, cretinism and iodine deficiency. Washington, DC: Pan American Health Organization (publication no. 502), 1986:373.
13. McCarrison R. Observations on endemic cretinism in the Chitral and Gilgit valleys. Lancet 1908;2:1275.
14. Choufoer JC, Van Rhijn M, Querido A. Endemic goiter in Western New Guinea. II. Clinical picture, incidence and pathogenesis of endemic cretinism. J Clin Endocrinol Metab 1965;25:385.
15. Buttfield IH, Hetzel BS. Endemic cretinism in Eastern New Guinea. Aust Ann Med 1969;18:217.
16. Bastenie PA, Ermans AM, Thys O, et al. Endemic goiter in the Uele region. III. Endemic cretinism. J Clin Endocrinol Metab 1962;22:187.
17. Dumont JE, Ermans AM, Bastenie PA. Thyroidal function in a goiter endemic. IV. Hypothyroidism and endemic cretinism. J Clin Endocrinol Metab 1963;23:325.
18. Delange F, Ermans AM, Vis HL, et al. Endemic cretinism in Idjwi Island (Kivu Lake, Republic of the Congo). J Clin Endocrinol Metab 1972;34:1059.
19. Ermans AM, Mbulamoko NM, Delange F, et al. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa, Ontario, Canada: International Development Research Centre, 1980.
20. Delange F, Iteke FB, Ermans AM. Nutritional factors involved in the goitrogenic action of cassava. Ottawa, Ontario, Canada: International Development Research Centre, 1982.
21. Vanderpas JB, Rivera-Vanderpas MT, Bourdoux P, et al. Reversibility of severe hypothyroidism with supplementary iodine in patients with endemic cretinism. N Engl J Med 1986;315:791.
22. Vanderpas JB, Contempré B, Duale NL et al. Iodine and selenium deficiency associated with cretinism in Northern Zaire. Am J Clin Nutr 1990;52:1087.
23. Delange F. Endemic goitre and thyroid function in Central Africa. In: Monographs in paediatrics. Vol. 2. Basel, Switzerland: Karger, 1974.
24. Shenkman L, Medeiros-Neto GA, Mitsuma T, et al. Evidence for hypothyroidism in endemic cretinism in Brazil. Lancet 1973;2:67.
25. Zhu XY. Endemic goiter and cretinism in China with special reference to changes of iodine metabolism and pituitary-thyroid function two years after iodine prophylaxis in Gui-Zhou. In: Ui N, Torizuka K, Nagataki S, Miyai K, eds. Current problems in thyroid research. Amsterdam: Excerpta Medical, 1983:13.
26. Fierro-Benitez R, Ramirez I, Garces J, et al. The clinical pattern of cretinism as seen in Highland Ecuador. Am J Clin Nutr 1974;27:531.
27. Lobo LCG, Pompeu F, Rosenthal D. Endemic cretinism in Goiaz, Brazil. J Clin Endocrinol Metab 1963;23:407.
28. Goslings BM, Djokomoeljanto R, Doctor R, et al. Hypothyroidism in an area of endemic goiter and cretinism in Central Java, Indonesia. J Clin Endocrinol Metab 1977;44:481.
29. Costa A, Cottino F, Mortara M et al. Endemic cretinism in Piedmont. Panminerva Med 1964;6:250.
30. Squatrito S, Delange F, Trimarchi F, et al. Endemic cretinism in Sicily. J Endocrinol Invest 1981;4:295.
31. Delange F, Valeix P, Bourdoux P, et al. Comparison of the epidemiological and clinical aspects of endemic cretinism in Central Africa and in the Himalayas. In: Hetzel BS, Smith RM, eds. Fetal brain disorders: recent approaches to the problem of mental deficiency. Amsterdam: Elsevier North Holland, 1981:243.
32. Ibbertson HK, Tait JM, Pearl M, et al. Himalayan cretinism. In: Stanbury JB, Kroc RL, eds. Human development and the thyroid gland: relation to endemic cretinism. New York: Plenum, 1972:51.
33. Stanbury JB, Fierro-Benitez R, Estrella E, et al. Endemic goiter with hypothyroidism in three generations. J Clin Endocrinol Metab 1969;29:1596.
34. Lagasse R, Roger G, Delange F, et al. Continuous spectrum of physical and intellectual disorders in severe endemic goitre. In: Ermans AM, Mbulamoko NM, Delange F, et al, eds. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa, Ontario, Canada: International Development Research Centre, 1980:135.
35. Trimarchi F, Vermiglio F, Finocchrio MD, et al. Epidemiology and clinical characteristics of endemic cretinism in Sicily. J Endocrinol Invest 1990;13:543.
36. Donati L, Antonelli A, Bertoni F, et al. Clinical picture of endemic cretinism in Central Apennines (Montefeltro). Thyroid 1992;2:283.
37. Delange F, Costa A, Ermans AM, et al. Clinical and metabolic patterns of endemic cretinism. In: Stanbury JB, Kroc RL, eds. Human development and the thyroid gland: relation to endemic cretinism. New York: Plenum, 1972:175.
38. Wang HM, Ma T, Li XT, et al. A comparative study of endemic myxedematous and neurological cretinism in Hetian and Luopu, China. In: Ui N, Torizuka K, Nagataki S, et al., eds. Current problems in thyroid research. Amsterdam: Excerpta Medica, 1983:349.
39. Shi ZF, Zeng GH, Zhang JX, et al. Endemic goiter and cretinism in Guizhou: clinical analysis of 247 cretins. Chin Med J 1984;97:689.
40. Ma T, Lu TZ, Tan YB, et al. Neurological cretinism in China. In: Kochupillai N, Karmakar MG, Ramalingaswami V, eds. Iodine nutrition, thyroxine and brain development. New Delhi: Tata McGraw-Hill, 1986:28.
41. DeLong GR, Stanbury JB, Fierro-Benitez R. Neurological signs in congenital iodine-deficiency disorder (endemic cretinism). Dev Med Child Neurol 1985;27:317.
42. DeLong GR. Observations on the neurology of endemic cretinism. In: DeLong GR, Robbins J, Condliffe PG, eds. Iodine and the brain. New York: Plenum, 1989:231.
43. DeLong GR. Neurological involvement in iodine deficiency disorders. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier, 1987:49.
44. Boyages SC, Halpern JP, Maberly GF, et al. A comparative study of neurological and myxedematous endemic cretinism in Western China. J Clin Endocrinol Metab 1988;67:1262.
45. Halpern JP, Morris JGL, Boyages S, et al. Neurological aspects of cretinism in Qinghai Province. In: DeLong GR, Robbins J, Condliffe PG, eds. Iodine and the brain. New York: Plenum, 1989:239.
46. Boyages SC. Iodine deficiency disorders. J Clin Endocrinol Metab 1993;77:587.
47. De Long GR, Ma T, Cao Xy, et al. The neuromotor deficit in endemic cretinism. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication, 1994:9.
48. Halpern JP, Boyages SC, Maberly GF, et al. The neurology of endemic cretinism. Brain 1991;114:825.
49. Rajatanavin R, Chailurkit L, Winichakoon P, et al. Endemic cretinism in Thailand: a multidisciplinary survey. Eur J Endocrinol 1997;137:349.
50. Boyages S. Iodine and the brain: evidence from the mountains of Thailand. Eur J Endocrinol 1997;137:336.
51. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;85:3975.
52. Ramirez I, Cruz M, Varea J. Endemic cretinism in the Andean region: new methodological approaches. In: Delange F, Ahluwalia R, eds. Cassava toxicity and thyroid: research and public health issues. Ottawa, Ontario, Canada: International Development Research Centre, 1983:73.
53. Downing D, Geel Hoed GW. Goiter and cretinism in the Uele Zaire endemia: studies of an iodine deficient population with changes following intervention. II. Functional and behavioral aspects. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication, 1994:233.
54. Smith DW, Blizzard RM, Wilkins L. The mental prognosis in hypothyroidism of infancy and childhood: a review of 128 cases. Pediatrics 1957;19:1011.
55. Vanderschueren-Lodeweyckx M, Debruyne F, Dooms L, et al. Sensorineural hearing loss in sporadic congenital hypothyroidism. Arch Dis Child 1983;58:419.
56. Raman G, Beierwaltes WH. Correlation of goiter, deafmutism and mental retardation with serum thyroid hormone levels in non-cretinous inhabitants of a severe endemic goiter area in India. J Clin Endocrinol Metab 1959;19:228.
57. Trowbridge FL. Intellectual assessment in primitive societies, with a preliminary report of a study of the effects of early iodine supplementation on intelligence. In: Stanbury JB, Kroc RL, eds. Human development and the thyroid gland: relation to endemic cretinism. New York: Plenum Press, 1972:137.
58. Pharoah POD, Hornabrook RW. Endemic cretinism of recent onset in New Guinea. Lancet 1973;2:1038.
59. Hetzel BS, Hay ID. Thyroid function, iodine nutrition and fetal brain development. Clin Endocrinol (Oxf) 1979;11:445.
60. Smith RM. Thyroid hormones and brain development. In: Hetzel BS, Smith RM, eds. Fetal brain disorders: recent approaches to the problem of mental deficiency. Amsterdam: Elsevier/North Holland Biomedical Press, 1981:149.
61. Potter BJ, McIntosh, Hetzel BS. The effect of iodine deficiency on fetal brain development in the sheep. In: Hetzel BS, Smith RM, eds. Fetal brain disorders: recent approaches to the problem of mental deficiency. Amsterdam: Elsevier/North Holland Biomedical Press, 1981:119.
62. Courtois P, Bourdoux P, Lagasse R, et al. Role of the balance between the dietary supplies of iodine and thiocyanate in the etiology of endemic goitre in the Ubangi area. In: Delange F, Iteke FB, Ermans AM, eds. Nutritional factors involved in the goitrogenic action of cassava. Ottawa, Ontario, Canada: International Development Research Centre, 1982:65.
63. Boyages SC, Maberly GF, Chen J, et al. Endemic cretinism: possible role for thyroid autoimmunity. Lancet 1989;2:529.
64. Boyages SC, Lens JW, Van Der Gaag RD, et al. Sporadic and endemic congenital hypothyroidism: evidence for autosensitization. In: Delange F, Fisher DA, Glinoer D, eds. Research in congenital hypothyroidism. New York: Plenum, 1989:123.
65. Medeiros-Neto G, Tsuboi K, Lima N. Thyroid autoimmunity and endemic cretinism. Lancet 1989;1:111.
66. Brown RS, Keating P, Mitchell E. Maternal thyroid-blocking immunoglobulins in congenital hypothyroidism. J Clin Endocrinol Metab 1990;70:1341.
67. Chiovato L, Vitti P, Marcocci C, et al. TSH-blocking antibodies and congenital hypothyroidism. In: Delange F, Fisher DA, Glinoer D, eds. Research in congenital hypothyroidism. New York: Plenum, 1989:141.
68. Chiovato L, Vitti P, Bendinelli G, et al. Humoral thyroid autoimmunity is not involved in the pathogenesis of myxedematous endemic cretinism. J Clin Endocrinol Metab 1995;80:1509.
69. Vanderpas JB, Contempré B, Duale NL, et al. Iodine and selenium deficiency associated with cretinism in Northern Zaire. Am J Clin Nutr 1990;52:1087.
70. Corvilain B, Contempré B, Longombe AO, et al. Selenium and the thyroid: how the relationship was established. Am J Clin Nutr Suppl 1993;57:244S.
71. Contempré B, Many MC, Vanderpas J et al. Interaction between two trace elements: selenium and iodine: implications of both deficiencies. In: Stanbury JB, ed. The damaged brain and iodine deficiency. New York: Cognizant Communication, 1994:133.
72. Dumont JE, Corvilain B, Contempré B. Endemic cretinism: the myxedematous and neurologic forms of a disease caused by severe iodine deficiency. In: Stanbury JB, ed. The damaged brain and iodine deficiency. New York: Cognizant Communication, 1994:133.
73. Goyens P, Golstein J, Nsombola B, et al. Selenium deficiency as possible factor in the pathogenesis of myxedematous endemic cretinism. Acta Endocrinol (Copenh) 1987;114:497.
74. Aaseth J, Frey H, Glattre E, et al. Selenium concentrations in the human thyroid. Biol Trace Elem Res 1990;24:147.
75. Dumont JE. The action of thyrotropin on thyroid metabolism. Vitam Horm 1971;29:287.
76. Arthur JR, Nicol F, Beckett GJ. Hepatic iodothyronine 5′-deiodinase: the role of selenium. Biochem J 1990;272:537.
77. Contempré B, Denef JF, Dumont JE, et al. Selenium deficiency aggravates the necrotizing effects of a high iodide dose in iodine deficient rats. Endocrinology 1993;132:1866.
78. Contempré B, Morreale de Escobar G, Denef JF, et al. Thiocyanate induces cell necrosis and fibrosis in selenium- and iodine-deficient rat thyroids: a potential experimental model for myxedematous endemic cretinism in Central Africa. Endocrinology 2004; 145:994.
79. Bernal J, Nunez J. Thyroid hormones and brain development. Eur J Endocrinol 1995;133:390.
80. Calvo R, Obregon MJ, Ruiz de Ona C, et al. Congenital hypothyroidism, as studied in rats: crucial role of maternal thyroxine but not of 3,5,3′-triiodothyronine in the protection of the fetal brain. J Clin Invest 1990;86:889.
81. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 1981;304:702.
82. Obregon MJ, Mallol J, Pastor R, et al. L-thyroxine and 3,5,3′triiodo-L-thyroxine in rats embryos before onset of fetal thyroid function. Endocrinology 1984;114:305.
83. Morreale de Escobar G, Pastor R, Obregon MJ, et al. Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. Endocrinology 1985;117:1890.
84. Ruiz de Ona C, Morreale de Escobar G, Galvo RM, et al. Thyroid hormones and 5′-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism. Endocrinology 1991; 128:422.
85. Morreale de Escobar G, Calvo RM, Obregon MJ, et al. Contribution of maternal thyroxine to fetal thyroxine pools in normal rats near term. Endocrinology 1990;126:2765.
86. Escobar del Rey F, Pastor R, Mallol J, et al. Effects of maternal iodine deficiency on the L-thyroxine and 3,5,3′-triiodo-L-thyroxine contents of rat embryonic tissues before and after onset of fetal thyroid function. Endocrinology 1986;118:1259.
87. Lavado-Autric R, Auso E, Garcia-Velasco JV, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 2003;111: 1073.
88. Versloot PM, Schröder-Van Der Elst JP, Van Der Heide D, et al. Effects of marginal iodine deficiency during pregnancy: iodide uptake by the maternal and fetal thyroid. Am J Physiol 1997;273:E1121.
89. Schröder-Van Der Elst JP, Vanderheiden D, Kastelijn J, et al. The expression of the sodium/iodide symporter is up-regulated in the thyroid of the fetuses of iodine-deficient rats. Endocrinology 2001;142:3736.
90. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Hormone nurturing of the developing brain: the rat model. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication, 1994:103.
91. Contempré B, Jauniaux E, Calvo R, et al. Detection of thyroid hormones in human embryonic cavities during the first trimester of gestation. J Clin Endocrinol Metab 1993;77:1719.
92. Bernal J, Pekonen F. Ontogenesis of the nuclear 3,5,3′-triiodothyronine receptor in the human fetal brain. Endocrinology 1984;114:677.
93. Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab 2002;87: 1768.
94. Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 1991;324:532.
95. Vulsma T, Gons MH, De Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989;321:13.
96. Man EB, Jones WS, Holden RH, et al. Thyroid function in human pregnancy. VIII. Retardation of progeny aged 7 years: relationship to maternal age and maternal thyroid function. Am J Obstet Gynecol 1971;111:905.
97. Matsuura N, Konishi J. Transient hypothyroidism in infants born to mothers with chronic thyroiditis: a nationwide study of twenty-three cases. Endocrinol Japon 1990;37:369.
98. Glinoer D, Delange F. The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid 2000;10:871.
99. Delange F, Thilly C, Bourdoux P, et al. Influence of dietary goitrogens during pregnancy in humans on thyroid function of the newborn. In: Delange F, Iteke FB, Ermans AM, eds. Nutritional factors involved in the goitrogenic action of cassava. Ottawa, Ontario, Canada: International Development Research, 1982:40.
100. Pharoah POD, Connolly KJ, Ekins RP, et al. Maternal thyroid hormone levels in pregnancy and the subsequent cognitive and motor performance of the children. Clin Endocrinol 1984;21: 265.
101. Pharoah POD, Ellis SM, Ekins RP, et al. Maternal thyroid function, iodine deficiency and fetal development. Clin Endocrinol (Oxf) 1976;5:159.
102. Thilly CH, Swennen B, Moreno-Reyes R, et al. Maternal, fetal and juvenile hypothyroidism: birth weight, and infant mortality in the etiopathogenesis of the IDD spectrum in Zaire and Malawi. In: Stanbury JB, ed. The damaged brain of iodine deficiency. New York: Cognizant Communication, 1994:241.
103. Thilly CH, Delange F, Lagasse R, et al. Fetal hypothyroidism and maternal thyroid status in severe endemic goiter. J Clin Endocrinol Metab 1978;47:354.
104. Glinoer D, De Nayer P, Delange F, et al. A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab 1995;80: 258.
105. Liu JL, Tan YB, Zuang ZL, et al. Morphologic study of development of cerebral cortex of therapeutically aborted fetuses in endemic region, Gui-Zhou Province, China. In: Ui N, Torizuka K, Nagataki S, Miyai K, eds. Current problems in thyroid research. Amsterdam: Excerpta Medica, 1983:390.
106. Kochupillai N, Pandav CS. Neonatal chemical hypothyroidism in iodine-deficient environments. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier, 1987:85.
107. Chaouki ML, Delange F, Maoui R, et al. Endemic cretinism and congenital hypothyroidism in endemic goiter in Algeria. In: Meideiros-Neto GA, Gaitan E, eds. Frontiers of thyroidology. New York: Plenum Press, 1986:1055.
108. Sava L, Delange F, Belfiore, et al. Transient impairment of thyroid function in newborn from an area of endemic goiter. J Clin Endocrinol Metab 1984;59:90.
109. Delange F, Beckers C, Höfer R, et al. Progress report on neonatal screening for congenital hypothyroidism in Europe. In: Burrow GN, Dussault JH, eds. Neonatal thyroid screening. New York: Raven, 1980:107.
110. Dussault JH, Mitchell ML, La Franchi S, et al. Regional screening for congenital hypothyroidism: results of screening one million North American infants with filter paper spot T4-TSH. In: Burrow GN, Dussault JH, eds. Neonatal thyroid screening. New York: Raven, 1980:155.
111. Thilly C, Vanderpas J, Bourdoux P, et al. Prevention of myxedematous cretinism with iodized oil during pregnancy. In: Ui N, Torizuka K, Nagataki S, Miyai K, eds. Current problems in thyroid research. Amsterdam: Excerpta Medica, 1983:386.
112. Wilkins L. Epiphyseal dysgenesis associated with hypothyroidism. Am J Dis Child 1941;61:13.
113. Courtois P, Delange F, Bourdoux P, et al. Significance of neonatal thyroid screening tests in severe endemic goiter [Abstract 81]. Ann Endocrinol 1982;43:51.
114. Delange F. Adaptation to iodine deficiency during growth: etiopathogenesis of endemic goiter and cretinism. In: Delange F, Fisher D, Malvaux P, eds. Pediatric thyroidology. Basel, Switzerland: Karger, 1985:295.
115. Braverman LE. Placental transfer for substances from mother to fetus affecting fetal pituitary-thyroid function. In: Delange F, Fisher DA, Glinoer D, eds. Research in congenital hypothyroidism. New York: Plenum, 1989:3.
116. Dumont JE, Ermans AM, Bastenie PA. Thyroid function in a goiter endemic. V. Mechanism of thyroid failure in the Uele endemic cretins. J Clin Endocrinol Metab 1963;23:847.
117. Vanderpas J, Bourdoux P, Lagasse R, et al. Endemic infantile hypothyroidism in a severe endemic goitre area of Central Africa. Clin Endocrinol (Oxf) 1984;20:327.
118. Moreno-Reyes R, Boelaert M, El Badawi S, et al. Endemic juvenile hypothyroidism in a severe endemic goitre area in Sudan. Clin Endocrinol (Oxf) 1993;38:19.
119. Vanderpas JB, Rivera-Vanderpas MT, Bourdoux P et al. Reversibility of severe hypothyroidism with supplementary iodine in patients with endemic cretinism. N Engl J Med 1986; 315:791.
120. Boyages SC, Halpern JP, Maberly GF, et al. Supplementary iodine fails to reverse hypothyroidism in adolescents and adults with endemic cretinism. J Clin Endocrinol Metab 1990;70:336.
121. Hetzel BS, Thilly CH, Fierro-Benitez R, et al. Iodized oil in the prevention of endemic goiter and cretinism. In: Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. New York: John Wiley & Sons, 1980:513.
122. Wespi HJ. Abnahme der Taubstumnheit in der Schweiz als Folge der Kropfprophylaxe mit iodertem Kochsalz. Schweiz Med Wochenschr 1945;75:625.
123. Ramirez I, Fierro-Benitez R, Estrella E, et al. The results of prophylaxis of endemic cretinism with iodized oil in rural Andean Ecuador. In: Stanbury JB, Kroc RL, eds. Human development and the thyroid gland: relation to endemic cretinism. New York: Plenum, 1972:223.
124. Pharoah POB, Buttfield IH, Hetzel BS. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971;1:308.
125. Ermans AM, Kinthaert J, Delcroix C, et al. Metabolism of intrathyroidal iodine in normal men. J Clin Endocrinol Metab 1968;28:169.
126. Fierro-Benitez R, Ramirez I, Estrella E, et al. The role of iodine deficiency in intellectual development in an area of endemic goiter. In: Dunn JT, Medeiros-Neto GA, eds. Endemic goiter and cretinism: continuing threats to world health. Washington, DC: Pan American Health Organization (publication no. 292), 1974:135.
127. Dodge PR, Palkes H, Fierro-Benitez R, et al. Effect on intelligence of iodine in oil administered to young Andean children: a preliminary report. In: Stanbury JB, ed. Endemic goiter. Washington, DC: Pan American Health Organization (publication no. 193), 1969:378.
128. Greene LS. Physical growth and development, neurological maturation and behavioral functioning in two Andean communities in which goiter is endemic. Am J Phys Anthropol 1973;38:119.
129. Bautista A, Barker PA, Dunn JT, et al. The effects of oral iodized oil on intelligence, thyroid status, and somatic growth in school-age children from an area of endemic goiter. Am J Clin Nutr 1982;35:127.
130. Muzzo S, Leiva L, Carrasco D. Possible etiological factors and consequences of a moderate iodine deficiency on intellectual coefficient of school-age children. In: Meideiros-Neto GA, Gaitan E, eds. Frontiers of thyroidology. New York: Plenum, 1985:1001.
131. Connolly KJ, Pharoah POD, Hetzel BS. Fetal iodine deficiency and motor performance during childhood. Lancet 1979;2: 1149.
132. Pharoah POD, Connolly K, Hetzel B, et al. Maternal thyroid function and motor competence in the child. Dev Med Child Neurol 1981;23:76.
133. Thilly CH, Roger G, Lagasse R, et al. Fetomaternal relationship, fetal hypothyroidism, and psychomotor retardation. In: Ermans AM, Mbulamoko NM, Delange F, et al, eds. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa, Ontario, Canada: International Development Research, 1980:111.
134. Bleichrodt N, Garcia I, Rubio C, et al. Developmental disorders associated with severe iodine deficiency. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier, 1987:65.
135. Boyages SC, Collins JK, Maberly GF, et al. Iodine deficiency impairs intellectual and neuromotor development in apparently normal persons. Med J Aust 1989;150:676.
136. Ma T, Wang YY, Wang D, et al. Neuropsychological studies in iodine deficiency areas in China. In: DeLong GR, Robbins J, Condliffe G, eds. Iodine and the brain. New York: Plenum, 1989:259.
137. Kochupillai N, Pandav CS, Godbole MM, et al. Iodine deficiency and neonatal hypothyroidism. Bull WHO 1986;64: 547.
138. Tiwari BD, Godbole MM, Chattopadhyay N, et al. Learning disabilities and poor motivation to achieve due to prolonged iodine deficiency. Am J Clin Nutr 1996;63:782.
139. Azizi F, Sarshar A, Nafarabadi M, et al. Impairment of neuromotor and cognitive development in iodine-deficient schoolchildren with normal physical growth. Acta Endocrinol (Copenh) 1993;125:501.
140. Thilly CH, Delange F, Golstein-Golaire J, et al. Endemic goiter prophylaxis by iodized oil: a reassessment. J Clin Endocrinol Metab 1973;36:1196.