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Introduction

Down syndrome is the single most common cause of severe learning disability, accounting for about one third of all cases of learning disability (Alberman, 1978). Seguin in 1866 described the condition now known as Down syndrome as "furfuraceous" cretinism, in an attempt to differentiate the condition from that of "stable" cretins. Unintentionally, therefore, over one-hundred and thirty years ago a link between Down syndrome and thyroid disease had been proposed. Langdon-Down (1866), influenced by the then prevalent "racial hypothesis" described the condition as "mongolism" and thought that affected people were a form of regression in evolution. During the early part of this century other endocrine disorders were implicated in the aetiology of Down syndrome. Some authors suggested that pituitary dysfunction was the main factor in the pathogenesis (Myers, 1938; Benda, 1946). The matter was finally resolved when in 1959 Lejeune and his co-workers (Lejeune et al, 1959) demonstrated that the syndrome was a result of trisomy of chromosome 21.

At the turn of the century, a pathological association between Down syndrome and thyroid disorders was described by Bournville (1903). Clinical and histo-pathological confirmation soon followed (Hill, 1908; Gordon, 1930; Pennacchietti, 1935; Benda, 1949). However, the first case of a person with Down syndrome and clinical hyperthyroidism was reported by Gilchrist in 1946 and of clinical hypothyroidism by Maranon et al, in 1951. At the turn of the third millennium thyroid disease in the Down syndrome population continues to be the focus of ongoing interest and research (Kennedy et al, 1992). This review collates previous research in the area of thyroid disorder and Down syndrome and explores aspects in need of further enquiry.

Prevalence studies

Over the last 30 years many publications have suggested an association between Down syndrome and thyroid disorders by showing altered levels of abnormal thyroxine (T4), triiodothyronine (T3) and/or thyroid stimulating hormone (TSH) levels (Table 1). Such changes may be present along with other hormonal and biochemical disturbances (Hestnes et al, 1991.)

There is a wide variation in reported prevalence rates of thyroid disorders in the Down syndrome population. Differences can be accounted for by the variability in the definitions of thyroid disorders employed in different studies, by the different populations (size, age) studied and by techniques used to measure given hormones and antibodies. Definitions or research diagnostic operational criteria for terms such as "hypothyroidism" are, therefore, useful; one such classification is shown in Table 2.

Hillman (1969) found that none of his 35 patients had thyroid dysfunction; Baxter et al (1975) found a rate of 66% in a sample size of eleven people with Down syndrome. Most studies report a prevalence rate higher than that in the general population. An evaluation of reported studies would suggest a lifetime prevalence of approximately 25-30%.

Tunbridge et al, (1977) found the prevalence of hypothyroidism in the general population (aged 18 years and older), to be 0.8%-1.1%, and the prevalence of hyperthyroidism as 1.1%-1.6%. A large study of congenital hypothyroidism in neonates with Down syndrome reported a prevalence of 0.12%; twenty-eight times greater than for the general population (Fort et al, 1984). The prevalence of acquired thyroid disorders increases with age, with higher rates being found for older persons with Down syndrome (Baxter et al, 1975; Korsager et al, 1978; Vladutiu et al, 1984; Dinani & Carpenter, 1990).

The prevalence of hypothyroidism has been found to be greater than that of hyperthyroidism. A ratio of 9% to 2% was proposed by Kinnell et al, (1987). Prasher (1994) investigated thyroid dysfunction in 160 adults with Down syndrome (mean age 43.4 years; age range 17-76 years). Thirty-five percent had evidence of thyroid dysfunction; subclinical hypothyroidism 12%, definite hypothyroidism 8%, hyperthyroidism 3%.

As well as an increase in the prevalence of hormonal abnormalities there is also an increased prevalence of autoimmune thyroiditis. Coleman and Abbassi (1984) found lymphocytic thyroiditis in 15 of 16 patients. Ivarsson et al (1997) found 39% of their sample of 70 children positive for thyroid antibodies and Vladitiu (1984) 38% of adults with Down syndrome. Detailed discussion on immunological aspects of Down syndrome is given later (see "immunological aspects"). In view of these findings children and adults with Down syndrome should be regularly tested for thyroid hormone and antibody status (see "management of thyroid disorders").

Reports of hypothyroidism and hyperthyroidism

As mentioned above, hypothyroidism is the commonest form of thyroid disorder associated with Down syndrome. The first case report of such an association was by Maranon et al (1951); this and the succeeding reports are listed in Table 3. Prevalence studies have shown that older individuals with Down syndrome are more prone to hypothyroidism, although most of the reports describe individuals below the age of 20 years and only one report is of a person over the age of 50 years. The female: male ratio is approximately 2:1.

Hypothyroidism may be either congenital (present at birth e.g. Verma & Ghal, 1971; King et al, 1978) or be acquired (occur at any age after birth). The neonatal screening programme by Fort et al (1984) found an incidence of congenital hypothyroidism of 1:141 live births (12 infants who had hypothyroidism out of 1130 live births). Three of the 12 infants with Down syndrome had transient hypothyroidism which resolved without intervention. Jaruratanasirikul et al (1998) detected congenital hypothyroidism in 17 of 112 (15%) babies with Down syndrome less than 1 year old. The majority had transient hypothyroidism. Thorpe-Beeston et al (1991) reported raised thyroxine stimulating hormone levels in all of the 5 fetuses with Down syndrome that they studied. Whether such an abnormality is involved in the subsequent development of learning disability and the possible value of intrauterine thyroid hormone supplementation remains to be studied. The aetiology of acquired hypothyroidism remains uncertain, although it is probably secondary to auto-immune thyroiditis (see "immunological aspects").

Gilchrist (1946) described the first case of a person with Down syndrome with a goitre secondary to hyperthyroidism. Table 4 lists other reports. Similar to case reports for persons with Down syndrome and hypothyroidism the majority of reports concern young individuals. There appears to be a greater female than male preponderance for hyperthyroidism than for hypothyroidism.

Clinical features of thyroid disorders in Down syndrome

Common features of hypothyroidism and hyperthyroidism are listed in Table 5.

In the past, similarities between Down syndrome and hypothyroidism led to misdiagnosis (Shuttleworth, 1909) and to subsequent inappropriate treatment of Down syndrome with thyroid extract (Benda, 1949). Smith (1896) is reported to be the first physician to treat the condition of "mongolism" with thyroid extract.

Recognition of thyroid disorders (especially hypothyroidism), can be very difficult; the person with Down syndrome is usually shorter in height, appears less active, has dry skin and fine hair, excess weight, bradycardia and mental impairment. These features are seen in hypothyroidism (Table 5) and therefore, make the early clinical diagnosis of hypothyroidism in individuals with Down syndrome difficult (Korsager & Andersen, 1979; Quinn, 1980; Mani, 1988, Prasher, 1995).

Mani (1988) in his study found that approximately 50% of 55 adult Down syndrome residents had clinical features suggestive of hypothyroidism (12% strong evidence, 38% mild evidence), and no cases of hyperthyroidism. Biochemically, however, only 22% had evidence of hypothyroidism (8 overt and 4 mild or subclinical). Prasher (1995) investigated the accuracy of diagnosing hypothyroidism in 201 adults with Down syndrome. Biochemical thyroid status was available for 160 subjects. For this group 57 were diagnosed has having clinical hypothyroidism but only 8 had underlying biochemical abnormalities. Five individuals with definite biochemical hypothyroidism showed no clinical evidence fore the disorder. A poor correlation between clinical hypothyroidism and biochemical hypothyroidism was found.

Neonatal screening tests for diagnosis of congenital hypothyroidism, although routinely done after birth, may not give an accurate reflection of thyroid function because of the TSH surge soon after birth. Clinical correlation with the tests could be spurious as the signs and symptoms of hypothyroidism in the new-born are not well developed. However, prolongation of physiological icterus, feeding difficulties, sluggishness, lack of interest, somnolescence and choking spells during nursing could be present during the first month. Respiratory problems due to large tongue, episodes of apnoea, noisy respiration and nasal obstruction could point towards a hypothyroid state in older infants. Affected infants cry little, sleep more, have poor appetite and show general sluggishness. Presence of an umbilical hernia, subnormal temperature and slow pulse point to the diagnosis of hypothyroidism in children with Down syndrome (Behrman et al, 1987). By the age of 6 months the clinical diagnosis of hypothyroidism could be easier. Older children may show severe retardation in growth with manifestation of hypothyroidism and may stand out in stark contrast to age related peers with Down syndrome in school activities.

Other abnormalities may suggest the presence of a thyroid disorder; eg, abnormal electrocardiogram consistent with hypothyroidism, (Murdoch, 1977), presence of a goitre (Ruvalcaba, 1969; Hollingworth, 1974), detection of a pericardial effusion (Werder et al, 1993), dementia (Prasher & Krishnan, 1993), detection of alopecia areata (du Vivier & Munro, 1975), premature puberty (Maranon et al, 1951).

Several aspects of thyroid disorders in the Down syndrome population have been further investigated. Criscuolo et al (1986) and Sharav et al, (1991) have suggested that in persons with Down syndrome subclinical primary hypothyroidism could be diagnosed by testing the hypothalamic-pituitary-thyroid pathway by detection of an exaggerated and prolonged TSH response to TRH (thyrotrophin releasing hormone).

Other studies have studied the role of trace elements in the aetiology of thyroid dysfunction. In particular alteration of zinc metabolism has been reported in studies of persons with Down syndrome (Napolitano et al, 1990; Licastro et al, 1992; Toledo et al, 1997; Sustrova & Strbak, 1994) and observed in both hyperthyroid and hypothyroid in non-Down syndrome patients (Dolev et al, 1988). Napolitano et al (1990) and Licastro et al (1992) have suggested that zinc deficiency may be a cause of thyroid disorders in Down syndrome. They found patients with Down syndrome had low zinc levels, and that zinc supplementation improved thyroid function and also reduced the incidence of infectious diseases and improved school attendance.

As thyroid disorders are difficult to diagnose in people with Down syndrome there should be a "high index of clinical suspicion". In view of the low cost of screening for thyroid disorders, the potential benefits of treatment, and the lack of a clear correlation between clinical and biochemical indications of thyroid disorders, thyroid function tests should be regularly performed (see management).

Other conditions possibly associated with Down syndrome and thyroid disorders

i) Premature puberty

Premature puberty has been reported in both girls and boys. In girls it can present with breast development, pubic hair, vaginal secretion, menstruation, acceleration of growth and in boys with pubic hair, testis enlargement and height spurt.

Barnes et al (1973) studied the association of early puberty with juvenile hypothyroidism in 54 children with primary hypothyroidism (one patient with Down syndrome); and found that 31 of them had evidence of iso-sexual maturation that was advanced when considered in relation to the "maturational" (bone) age. They concluded that long-standing thyroid failure induces increased TSH secretion, both indirectly (through the action of thyrotropin - releasing hormone) and directly (at the level of the pituitary) and this action on pituitary may induce subsequent premature sexual development.

Several case reports of premature puberty in children with Down syndrome who were also identified to have hypothyroidism have been reported (Table 6). It is reasonable to assume the mechanism behind such a possible association is similar to that described by Barnes et al (1973). Any association is likely not to be a common occurrence but professionals in contact with children with Down syndrome who are diagnosed has having a thyroid disorder should be alert to the possibility of other endocrine disorders.

ii) Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterised by high blood sugar levels due usually to insulin deficiency. Common symptoms include large amounts of urine excretion, thirst and weight loss. Case reports of the occurrence of diabetes in persons with Down syndrome with hypo or hyperthyroidism have been reported (Table 6). An association between autoimmune thyroid disease and diabetes mellitus is well recognised and it is likely, for people with Down syndrome, that a generalised autoimmune disorder is the underlying cause. Appropriate management by a specialist diabetic service is required to prevent serious complications.

iii) Dementia (Alzheimer's disease)

Untreated hypothyroidism resulting in intellectual decline is now recognised to occur in adults with Down syndrome (Thase 1982a, Prasher & Krishnan, 1993). Appropriate treatment can lead to significant improvement. The commonest form of dementia- Alzheimer's disease- is particularly prevalent in older adults with Down syndrome (Oliver & Holland, 1986; Prasher & Krishnan, 1993). Research in the general population has suggested that thyroid disorders may predispose to AD (Heyman et al, 1983; Mortimer, 1990). There is no definite evidence showing that thyroid disorders predisposes to AD in the Down syndrome population. However, Percy et al (1990) suggested that "subclinical" hypothyroidism may contribute to cognitive deficits in ageing Down syndrome patients and Bhaumik et al (1991) have shown that elevated levels of TSH in a group of patients with Down syndrome inversely correlated with scores of global adaptive abilities. Although further research is required, it is unlikely that thyroid hormone estimation is of any clinical value as a peripheral marker of Alzheimer's disease (Prasher, 1995).

iv) Other conditions

Several case reports have been published illustrating the occurrence of Down syndrome, thyroid dysfunction (hyperthyroidism or hypothyroidism) and other physical disorders (Table 6). Large scale epidemiological studies are required to fully investigate definite associations but it is possible there is an underlying impairment of autoimmune function leading to multi-systemic dysfunction. From reports to date particular associated conditions are early puberty, diabetes mellitus and cardiac disease. For the general population an association between thyroid dysfunction and depression has been reported but no such association was found for adults with Down syndrome (Prasher & Hall, 1996).

Immunological aspects

An association between Down syndrome and immunological disorders, in particular susceptibility to infections, malignancies and autoimmunity, has been highlighted by many researchers (Gershwin et al, 1977; Ugazio et al, 1992). The underlying cause is still to be fully described but is related to T cell derangement, abnormalities with antibody-mediated immunity and dysfunction of phagocytosis (Wisnewiski et al, 1979; Rabinowe et al, 1989; Ugazio et al, 1992). The susceptibility to autoimmune thyroiditis being further related to as yet unidentified specific genes on chromosome 21 (Nicholson et al, 1994).

The relationship between Down syndrome and autoimmune thyroid disease is irrespective of the underlying karyotype (Robertson et al, 1965) and was first described by Mellon et al (1963). The association has been confirmed by subsequent reports (Table 7). Hashimoto's thyroiditis (lymphocytic thyroiditis), was first described by Roitt et al in 1956, and is also a common condition in the Down syndrome population (Saxena & Crawford, 1962; Leboeuf & Bongiovanni, 1964).

Persons with Down syndrome with circulating thyroid autoantibodies may present with hypothyroidism (Baxter et al 1975; Murdoch et al, 1977;