European Journal of Endocrinology (1997) 137 349355

ISSN 0804-4643

Endemic cretinism in Thailand: a multidisciplinary survey

Rajata Rajatanavin1, La-or Chailurkit1, Pradit Winichakoon5, Pat Mahachoklertwattana2, Suchart Soranasataporn1, Rames Wacharasin3, Valaiporn Chaisongkram5, Poonpit Amatyakul4 and Luecha Wanarata5
Departments of 1Medicine, 2Pediatrics, 3Radiology and 4Otolaryngology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, and 5The Ministry of Public Health, Thailand (Correspondence should be addressed to R Rajatanavin, Department of Medicine, Ramathibodi Hospital, Rama 6th Road, Bangkok 10400, Thailand)

Abstract
Endemic cretinism has been classied into neurological and myxedematous types. Profound mental deciency, deaf-mutism and cerebral diplegia are predominantly found in the former. The latter have been described as less mentally retarded but with severe growth retardation and myxedematous features. The pathogenesis of different clinical types of endemic cretinism is still unclear. Recently, a unifying hypothesis suggested that iodine deciency, severe enough to cause maternal and fetal hypothyroxinemia, results in neurological defects in all cretins. We conducted the present study in northern Thailand to determine the validity of this hypothesis in another geographical area. The study consisted of a multidisciplinary survey on 112 endemic cretins aged 266 years in Nan. They were categorized clinically into three types of endemic cretins, neurological (n = 57), myxedematous (n = 19) and mixed form (n = 36). The subjects were generally short and the majority had severe mental retardation (mean intellectual quotient (I.Q.) 30.8 8.8), psychomotor defect and profound sensorineural hearing loss. The I.Q. score and proportion of cretins with sensorineural hearing loss and psychomotor defect were similar among the three types of cretins. The most frequent neurological abnormalities were spasticity, hyper-reexia, the presence of primitive reexes and gait disturbance. These abnormalities were distributed equally among the three types of endemic cretins. Delayed skeletal maturation and abnormal epiphysis were also present in all types of cretins. However, myxedematous cretins were shorter (P < 0.01), having more myxedematous features (P < 0.05 to P<0.001) and less sexual maturation (P < 0.05). Thyroid volume was lower in cretins with hypothyroidism (P < 0.01). In conclusion, our ndings support the hypothesis that neurological features are present in all types of cretins, and are the consequence of maternal and fetal hypothyroxinemia due to severe iodine deciency. The clinical manifestations of the cretins were subsequently modied by the length and severity of postnatal iodine deciency and hypothyroidism. European Journal of Endocrinology 137 349355

Introduction
Endemic cretinism is the most severe result of iodine deciency. It has been classied into two clinical types, neurological and myxedematous cretinism (1). Neurological cretins are characterized by profound mental deciency, deaf-mutism, cerebral diplegia but clinical euthyroidism. In contrast, myxedematous cretins are traditionally described as less mentally retarded but with severe growth retardation and other signs of hypothyroidism. The prevalence of different types of endemic cretinism also varies geographically. Myxedematous cretins are primarily found endemic in Nepal, central Africa and western China (24) while neurological cretins are more ubiquitous. There is controversy about the pathophysiology of the different types of endemic cretinism and also about their different geographical distribution (5), and it has been claimed that a single theory cannot explain all the abnormalities observed. Recently, Boyages & Halpern
1997 Society of the European Journal of Endocrinology

(6) have proposed a unifying hypothesis for the pathophysiology of endemic cretinism based on their extensive study of endemic cretinism in western China (7). They found that, contrary to common belief, the degree of mental retardation and the frequency of neurological abnormalities are found in both types of endemic cretinism. They suggested that all neurological abnormalities occurred in utero due to both maternal and fetal hypothyroxinemia secondary to severe iodine deciency. Postnatally, the persistence of hypothyroidism, either from continuing iodine deciency or other mechanisms causing thyroid failure, entails the development of myxedematous cretinism. Endemic cretinism is present in northern Thailand. We conducted a multidisciplinary survey, namely clinical, biochemical, audiological, psychological and radiological examination of endemic cretinism, in the Nan province. Our purpose was to determine the validity of the unifying hypothesis of endemic cretinism proposed by Boyages & Halpern (6).

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Subjects and methods

Study area
Nan province is situated in the northern mountainous area of Thailand. The total goiter rate in Nan was 36.4% and the total number of cretins was 456. The prevalence of cretinism was as high as 0.1% in one district (8). The study was performed in three districts, Pua, Toongchang and Santisuk.

Table 1 Demographic data of endemic cretins in this study. Values are means S.D. with the range in parentheses.
Types of endemic cretins Neurological (n 57) Myxedematous (n 19) Mixed (n 36)

Age (years) Height (cm) Sitting height (cm)

Classication of cretins
One hundred and twelve cretins were recruited by local health ofcers. They were then examined by local physicians who classied them into three classical types, neurological, myxedematous and mixed types, by a standard guideline based on the denition of endemic cretinism proposed by the Pan American Health Organization (9). The demographic data of the cretins in this study is shown in Table 1.

Arm span (cm) Head circumference (cm)

a

34.2 12.6 (1366) 149.0 8.6a (110163.5) 79.5 4.5a (6287.5) 152.2 9.6 (111169) 54.5 6.4 (4699)

39.6 17.8 (264) 131.5 22.4b (79153) 70.4 10.6b (4981) 132.4 23.9 (73.5158) 52.9 2.1 (4755.2)

33.6 9.5 (1350) 144.4 9.6 (121160.7) 78.5 5.1 (61.587) 149.9 11.8 (121172) 54.2 2.0 (46.558)
b

P < 0:01 compared with myxedematous cretins; compared with mixed cretins.

P < 0:01

Multidisciplinary examination
A research team from the Ramathibodi Hospital comprised of adult and pediatric endocrinologists, neurologists, an otolaryngologist, psychologists and a radiologist examined the cretins without prior knowledge of their classication. General physical and endocrinological examinations were extensively performed, including goiter palpation and assessment of testicular size in men by orchidometry. Full neurological and detailed otolaryngologic examinations were also performed. Hearing ability (air and bone conduction threshold (frequencies 250 8000 Hz) was measured by a portable clinical pure tone audiometer (Maico, USA) which had been calibrated per Ansi standard, USA of 1969, ISO 1978, and 1981. Intellectual quotient (I.Q.) was assessed by the Arthur point scale of performance test (10) and visualperceptive neuromanual ability was assessed by the Bender Gestalt Test (11). Radiological examinations included plain X-rays for lateral skull, hips and left hands. The degree of bone maturation was assessed by the criteria of Greulich & Pyle (12). Goiter volume was determined by ultrasonography using a portable ultrasonography machine (Hitachi EUB 200) with a 5 MHz tranducer. Calculation of goiter volume was based on Brunns equation (13). Blood was collected from all cretins and sera were kept frozen for the determination of thyroxine (T4), free T4 and thyrotropin (TSH) concentrations. Serum T4 was measured by the Amerlex-M T4 kit from Johnson & Johnson Clinical Diagnostics Inc., USA. Serum-free T4, T3 and TSH concentrations were measured by chemiluminescent assays (Johnson & Johnson Clinical Diagnostics Inc.) Serum anti-TPO and anti-Tg antibodies

were determined by RIA (RSR Ltd, UK). The cut-off level for positive anti-TPO and anti-Tg antibodies was 0.3 U/ ml.

Statistical analyses
Comparisons between groups were evaluated by Students t-test for normal distribution data or Mann Whitney rank sum test for skewed data. ANOVA was

Table 2 I.Q. scores and proportion of endemic cretins with psychomotor defects. Data are means S.D.; the numbers in parentheses are ranges.
Types of endemic cretins Neurological (n 57) I.Q. Proportion of cretins with psychomotor defect (%) Borderline Defective Right ear Sensorineural hearing loss (%) Mildmoderate Moderatesevere Profound Conductive hearing loss (%) Left ear Sensorineural hearing loss (%) Mildmoderate Moderatesevere Profound Conductive hearing loss (%) 32.3 9.38 (1461) Myxedematous (n 19) 30.6 8.3 (1343) Mixed n 36) 28.6 7.8 (1055)

22.8 75.4

5.3 94.7

11.1 88.9

8.8 12.3 73.7

5.3 26.3 57.9 5.3

8.3 16.7 72.0

12.3 22.8 59.6

5.3 47.4 42.1 5.3

8.3 25.0 63.9

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Figure 1 Myxedematous features (coarse skin, dry skin, coarse hair and soft cartilage) were present in a greater proportion in myxedematous cretins than in neurological and mixed cretins.

used for comparison between subgroups. Differences between two proportions were evaluated by chi-square analysis. All statistical calculations were done by computer using the Statistical Package for the Social Sciences Program.

Results
General physical appearances and endocrine manifestations
All three types of cretins were shorter than age-matched normal Thai subjects (14). However, myxedematous cretins were shortest (Table 1). Myxedematous features were found more in myxedematous cretins as demonstrated in Fig. 1. Also, less sexual maturation as indicated by a smaller testicular volume was observed in myxedematous cretins (Fig. 2).

Figure 2 Testicular volume as measured by orchidometry in male myxedematous cretins had a tendency to be lower than in neurological and mixed cretins and reached statistical signicance on the left side. The data are means S.E.M.

Neurological examination
Different types of neurological abnormalities were observed in all three types of cretins. Notably, defects in extrapyramidal tract and primitive reexes were most frequently present. The details of neurological abnormalities are provided in Table 3. The proportion of cretins with abnormal neurological signs were not different among the three types of cretins. However, the number of cretins with motor abnormalities (weakness and spasticity) was greater in mixed cretins (Fig. 3).

Psychological examination
The majority of cretins had severe mental retardation with a mean I.Q. score of 30.88.8. The I.Q. score and proportion of cretins with a psychomotor defect were similar among the three types of cretins as demonstrated in Table 2.

Biochemical ndings
Data on serum T4, free T4, T3 and TSH concentrations and thyroid autoantibodies are demonstrated in Table 4. Myxedematous cretins had lower serum T4 and free T4 levels than neurological cretins, and lower serum T3 levels than mixed cretins. Myxedematous cretins also had the highest levels of serum TSH. The percentage of

Otology-audiology examination
The proportion of cretins with bilateral sensorineural hearing loss was similar among the three types of cretins. This was also the case with conductive hearing losses (Table 2).

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Table 3 Some neurological abnormalities in neurologic, myxedematous and mixed cretins.

Neurologic cretins
(n 57) Gait Wide base Knock knee Spastic Everted feet Motor Spasticity Babinskis sign Brisk knee reexes Primitive reexes Glabella Grasping Palmarmental Bradykinesia Dysdiodokokinesia Dysarthria Percussion myoedema 10 8 27 8 42 10 22 27 1 12 14 9 9 13

Myxedematous cretins
(n 19) 3 3 5 4 13 3 5a 7 1 4 3 2 4 3

Mixed cretins
(n 36) 8 3 25 12 31 8 26b 15 4 10 9 7 4 8

The proportion of cretins with abnormal neurological signs were not different among the three types except brisk knee reexes: a P < 0:01 compared with mixed cretins; b P < 0:01 compared with neurological cretins.

cretins with detectable circulating thyroid autoantibodies was similar among the three types of cretins.

X-rays ndings and ultrasonography

The number of cretins with abnormal X-rays was not different among the three types (18%, 44%, and 32% in

neurological, myxedematous and mixed cretins respectively). The abnormalities included coxa vara, coxa vulga, strippled epiphyses, enlarged sella turcica and delayed bone age. Cretins were classied into two groups according to their thyroid function test. The euthyroid group consisted of 95 cretins and the hypothyroid group 17 cretins. The mean serum T4 and TSH levels in the euthyroid cretins were 94 21 (S.D.) nmol/l and 1.3 0.7 mU/l respectively and the levels in the
Table 4 Thyroid function tests and circulating thyroid autoantibodies in three clinical types of endemic cretinism. Data are means S.D.; the numbers in parentheses are ranges.
Types of endemic cretins Neurological (n 57) Myxedematous (n 19) Mixed (n 36)

T4 (nmol/l) Free T4 (pmol/l) T3 (nmol/l) TSH (mU/l) Anti-TPO antibody (%)* Anti-Tg antibody (%)* Figure 3 The frequency of neurological defects were distributed similarly among the three types of cretins. However, the number of cretins with motor abnormalities (weakness and spasticity) was greater in the mixed cretins.

101 40 (52338) 21.2 11.6a (10.3101.9) 2.3 1.4 (1.112.0) 2.1 4.7 (UD 29.7) 7.0 10.5

75 31 (13115) 15.5 6.5 (0.721.9) 1.8 0.6b (UD 2.6) 41.8 118.0 (0.6499) 10.5 10.5

96 27 (22150) 19.3 7.7 (2.651.6) 2.2 0.6 (1.24.5) 2.6 22.6 (UD 2.26) 5.6 13.8

* Numbers of cretins with circulating thyroid autoantibodies above normal; anti-TPO and anti-Tg antibodies >0.3 U/ml were considered positive. UD = undetectable (TSH < 0.04 mU/l). a P < 0:05 compared with myxedematous cretins; b P < 0:05 compared with mixed cretins.

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Figure 4 Hypothyroid cretins (n = 17) had signicantly lesser goiter volume as measured by ultrasonography than euthyroid cretins (n = 95). The data are means S.E.M.

hypothyroid cretins were 67 39 nmol/l and 67.8 137.2 mU/l respectively. The thyroid volume of hypothyroid cretins as assessed by ultrasonography was signicantly less than their euthyroid counterparts (9.9 8.4 ml vs 23.8 18.9 ml, P < 0.01) (Fig. 4).

Discussion
The essential nding of this study was a similar frequency of low intelligence, defects in visual-perceptive neuromanual ability, sensorineural hearing loss and neurological defects in all three types of endemic cretinism. However, growth retardation, myxedematous features and sexual immaturity were found at a much greater frequency in myxedematous cretins. Our conclusion concurred with an earlier study of similar design performed by Boyages et al. in China (7) and two recent studies from Italy (15, 16). In addition, neurological abnormalities frequently found in cretins (gait disorder, spasticity, hyper-reexia, primitive reexes) were similar to those reported earlier (3, 7, 15, 16). The similar frequency of intelligence and neurological deciency in all types of cretins pointed to a primary pathophysiologic event, which probably occurred in utero. Many studies have indicated that the critical period of the adverse effect of iodine deciency on brain development is during early gestation. The classic study by Pharoah et al. (17) in Papua, New Guinea clearly demonstrated that iodine must be given before conception rather than during pregnancy to be effective in the prevention of endemic cretinism. A recent study in western China documented that iodine must be given to the pregnant mother in the second trimester to prevent neurological damage (18). Treatment later in pregnancy or after delivery may improve brain growth and

developmental achievement slightly, but it does not improve neurologic status (18). These data indicate that thyroid hormones are essential for brain development in utero during early pregnancy before the onset of fetal thyroid function, which commences at week 12 of gestation (19). Both T4 and T3 have been detected in rat embryo (20) and fetal rat brain (21) before the onset of fetal thyroid function. Morreale de Escobar et al. (22) demonstrated that maternal hypothyroxinemia due to iodine deciency resulted in lack of thyroid hormone in fetal tissues during early pregnancy, even before the onset of fetal thyroid function. In addition, specic T3 receptors have been found in rat (23) and human fetal brain early in gestation (24). More recently, Contempre et al. (25) have demonstrated the presence of thyroid hormone in human embryonic cavities as early as the second month of pregnancy, long before the onset of fetal thyroid function. Vulsma et al. (26) have demonstrated signicant levels of T4 during late pregnancy in cord sera of neonates born with congenital absence of the thyroid or a total organication defect. The T4 levels progressively declined after birth and became undetectable within 2 weeks. Morissette & Dussault (27) also provided data to demonstrate maternalfetal T4 transfer in athyrosis. Thus it seems that T4 can be transferred through the placenta throughout gestation at least to some degree. This view is emphasized by a recent report of severe clinical hypothyroidism in a neonate born with fetomaternal hypothyroxinemia due to Pit-1 deciency (28). It is well documented that neonates born with sporadic congenital hypothyroidism appear normal at birth, only 5% will be detected clinically (29). In addition, neurological damage is rarely evident in sporadic congenital hypothyroidism. This indicates that, unlike in endemic cretinism, maternal T4 has helped to alleviate fetal hypothyroidism in utero. Postnatally, persistent hypothyroidism, either from iodine deciency or from other causes of thyroid gland failure, results in myxedematous manifestations of endemic cretinism. In contrast, restoration of thyroid function occurs postnatally in neurological cretins (6). The etiology of thyroid failure in myxedematous cretins remains speculative. The possibilities include thiocyanate toxicity (30) and selenium deciency (31). Some investigators (32, 33) but not others (34) have provided evidence of immunological mechanisms causing destruction of the thyroid. The mechanism of the lack of adequate thyroid compensation in myxedematous cretins in Thailand is not known. The number of cretins with circulating thyroid autoantibodies were also similar among the three types. Selenium deciency has received much attention lately. Glutathione peroxidase of the thyroid gland, helping to neutralize hydrogen peroxide radicals, is a selenoenzyme (35). Lack of selenium results in both decreased thyroid peroxidase activity, allowing peroxide radicals to accumulate, as well as in induced thyroid cell

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brosis (36). Selenium is also a component of the type I deiodinase enzyme which converts T4 to T3 (37). A decrease in the activity of this enzyme in selenium deciency in combination with iodine deciency may help in restoring T4 levels to the brain, thus protecting it from further neurological damage (38). Glutathione peroxidase activity was found to be decreased in selenium-decient areas in Zaire, and the enzyme activity in cretins was half the level in normal subjects (38). Combined iodine and selenium deciency could thus explain the large predominance of the myxedematous cretin as typically seen in Zaire. However, neurological cretinism was predominantly found in endemic areas of both iodine and selenium deciency in China (39). In addition, our study, which indicated similar degrees of mental and neurological abnormality in both traditional types of cretins, does not support the contention that selenium deciency protects against the neurological damage of iodine deciency in some manner. Other environmental factors may therefore be responsible for thyroid atrophy in such patients. In this context, two independent investigators have demonstrated that reversibility of severe hypothyroidism with iodine supplement could be accomplished only before 4 years of life in patients with endemic cretinism (40, 41). This age-dependent reversibility of severe hypothyroidism with iodine supplementation supports the hypothesis that a progressive loss of functional capacity of the thyroid occurs in patients with myxedematous cretinism. Our study therefore supports the hypothesis that neurological defects, common to all types of cretins, are the result of the combination of maternal and fetal hypothyroxinemia secondary to iodine deciency, whereas the degree of myxedematous features is due to the length and severity of postnatal hypothyroidism (6). Our study also indicates that the pathogenesis of endemic cretinism is universal and similar in different geographical areas of the world.

Acknowledgements
This work was supported by The Prajadhipok-Rambhai Barni Foundation. The authors wish to thank Drs Chanchai Jariengprasert, Saengsom Sinawat and Mrs Anocha Wipulakorn for their valuable help in this study.

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Received 23 December 1996 Accepted 28 April 1997