Down Syndrome and Thyroid Disorders: A Review

Vee Prasher

Thyroid disorders are common in the Down syndrome population but many specific areas of importance remain to be resolved. A detailed review of previously published case reports and research studies highlighting the clinical association between Down syndrome and thyroid disorders was undertaken. Historical, epidemiological, immunological, diagnostic and treatment issues are addressed. Recommendations for future management and research are considered.

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Prasher, V. (1999) Down Syndrome and Thyroid Disorders: A Review. Down Syndrome Research and Practice, 6(1), 25-42. doi:10.3104/reviews.95

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; Lobo et al, 1980; Dinani & Carpenter, 1990), hyperthyroidism (Aarskog, 1969; Blumberg & Ruskin, 1987) or may be euthyroid (Hollingsworth et al, 1974). Further, not all individuals with clinical thyroid disease have auto-antibodies (Cutler et al, 1986). Thyroid auto-antibodies may be either anti-thyroid globulin antibodies (ATAs) or anti-microsomal antibodies (AMAs). There maybe elevated ATAs and AMAs or increased ATAs or AMAs only.

In Pueschel & Pezzullo's study (1985) of 47 patients (of a total sample of 151) with elevated thyroid antibodies 14 had both elevated ATA and AMA titres, 5 with increased ATA titres and 28 had elevated AMA titres. Vladutiu et al (1984) detected thyroid antibodies in 16 of 42 patients (38%) and 9 persons were positive for ATAs. Only 5 patients (12%) were positive for both ATAs and AMAs whereas 4 had only ATAs and 7 only AMAs. In the 5 subjects positive for thyroid antibodies no evidence of hypothyroidism was found.

The relationship between certain chromosomal abnormalities (especially Down syndrome and Turner's Syndrome) and thyroid autoimmunity has been reviewed by Bright et al (1982). There are several hypotheses that attempt to describe this association; (i) chromosomal abnormalities may result in secondary autoimmune disease (ii) pre-existing autoantibodies in the mother may predispose to a chromosomal abnormality in the child (iii) both aneuploidy and autoimmune disease may be a result of another (unknown) process. There is little evidence to favour any one of these hypotheses over the others at present, although some studies have shown an increase in frequency of thyroid autoantibodies in mothers of patients with Down syndrome (Mellon et al, 1963; Doniach et al, 1965; Fialkow, 1970; Vanhaelst et al, 1970).

Hepatitis B and autoimmune thyroiditis occur frequently in the Down syndrome population. Several studies (Fialkow et al, 1971; Ugazio et al, 1977; Sutnick et al, 1972; Ferris et al, 1972; Hollingsworth et al, 1974), have demonstrated an increase in the presence of the Hepatitis B surface antigen (HBsAg; Australia antigen) in the Down syndrome population, compared to controls. Hollingsworth et al (1974) found HBsAg positive in 16 of 60 (27%) of their Down syndrome patients but in none of their learning disabled controls. Thyroid antibodies were present in 5 of 6 patients with Down syndrome and in only one of 60 controls.

May and Kawanishi (1996) investigated a possible association between HBsAg and thyroid autoimmunity in 57 adults with Down syndrome. They found the frequency of autoimmune thyroiditis in patients with Down syndrome who were also carriers of hepatitis B surface antigen (HBsAg) was threefold higher than the frequency of thyroid disease patients with Down syndrome who were not carriers of HBsAg (65% v 23%). The significance of these findings is unclear but chronic exposure to HBsAg may lead to autoimmune thyroid disease in persons with Down syndrome.

Genetic aspects

Hereditary factors, as in the general population (Doniach et al, 1965), appear to play a part in the aetiology of thyroid disorders in the Down syndrome population. Several studies have shown significantly higher thyroid disorders and thyroid autoimmune disease in the parents or siblings of affected individuals (Table 7).

The precise role of hereditary factors remain uncertain but several hypotheses have been previously proposed. One fascinating hypothesis was by Fialkow in 1966 when he hypothesised that thyroid disorders in the mothers of children with Down syndrome ante-dates the birth of a child with Down syndrome and predispose to gamete/chromosome abnormality and thereby to a child with Down syndrome. Although support for this controversial hypothesis was given by other investigators (Engel, 1967; Dallaire et al, 1969; Flannery et al, 1984, 1986) recent, more methodologically improved studies, found little evidence of support. Torfs et al (1990) measured levels of thyroid antibodies in serum samples drawn during early pregnancy from 101 gravidas who delivered a child with a trisomy, from 11 gravidas who had had a trisomic child in a previous pregnancy, and from 44 fathers was investigated along with serum from matched controls. Overall, there was no association between the presence of thyroid antibodies in a mother and a trisomy birth. Case fathers, as compared with control fathers, did not have a higher prevalence of thyroid antibodies. Gustafsson et al (1995) measured the incidences of thyroglobulin and thyroid peroxidase antibodies in 29 mothers giving birth to children with trisomy 21 and in 87 control mothers. Samples collected at delivery. There was no statistical difference regarding the proportion of thyroid antibodies in the two groups. The authors concluded that the presence of thyroid antibodies in the serum of a pregnant woman has no prognostic value for the birth of an infant with Down syndrome.

Most cases of trisomy 21 are due to maternal non-disjunction at first meiosis and the role of maternal age effect is unexplained. The proposition that lack of chiasma formation at a critical stage of chromosome separation could lead to Down syndrome (Hulten, 1990) suggests the possibility of maternal age-related disease having a mechanical effect in the process of disjunction. The effect of varying concentrations of thyroxine on the process of gamete formation needs further animal and tissue culture studies and could still provide considerable evidence for Fialkow's hypothesis.

Management of thyroid disorders

With the advent of chromosomal analysis and the ready availability of thyroid function tests, inappropriate diagnosis and treatment of thyroid disorders in persons with Down syndrome should no longer occur. Results of thyroid function tests may need to be interpreted with caution especially in individuals who are already susceptible to acute illnesses and are often taking one or more drugs. Hormone levels may fluctuate and abnormalities be transient. Monitoring may in many cases be all that is required.

Once the diagnosis of a thyroid disorder has been made, depending on its severity and type (hypothyroidism or hyperthyroidism, presence or absence of thyroid antibodies) management is generally similar to that in the general population (Rae et al, 1993).

i) Hypothyroidism

Definite hypothyroidism is treated with thyroxine replacement and usually needed for life. Improvement is seen in physical symptoms (Korsager & Andersen, 1979), regrowth of hair (Scotson, 1989), improvement in cognitive functioning (Thase, 1982b; Prasher & Krishnan, 1993) and social functioning (Prasher & Krishnan, 1993). The clinical benefit of zinc supplementation in the management of hypothyroidism in individuals with Down syndrome requires further investigation (Napolitano et al, 1990; Sustrova & Strbak, 1994).

ii) Hyperthyroidism

Hyperthyroidism is treated with measures to reduce thyroxine activity, Medically with carbimazole, propylthiouracil or radioactive iodine (Diggle & Weetch, 1958; Nibhanupudy et al, 1986; Bhomwmick and Grubb, 1997). Surgical intervention involves partial thyroidectomy but this is rarely undertaken in patients with Down syndrome. The principal complication of these forms of treatment for hyperthyroidism is resultant hypothyroidism (Bhomwmick & Grubb, 1997).

iii) Subclinical Hypothyroidism

Controversy remains regarding the management of subclinical hypothyroidism. Recent longitudinal studies of thyroid dysfunction in the Down syndrome population ( Rubello et al, 1995 ; Prasher, 1996; Selikowitz, 1993) suggest that subclinical hypothyroidism is a common transient condition in people with Down syndrome. Evidence would suggest it can occur with or without presence of thyroid autoimmunity. Selikowitz (1993) in a 5 year longitudinal study of 101 children found 8 children developed subclinical hypothyroidism which in half resolved spontaneously at the end of the study period. Rubello et al (1995) found that in the presence of thyroid autoimmunity, a significant number of individuals with Down syndrome and with subclinical hypothyroidism can develop definite hypothyroidism or hyperthyroidism. In individuals with absence of thyroid autoimmunity spontaneous normalization of TSH levels can occur.

Appreciable benefit following treatment of subclinical hypothyroidism with thyroid hormone supplementation remains in doubt (Tirosh et al, 1989). These researchers failed to show any efficacy of short-term thyroid hormone therapy for this population as assessed in a double-blind cross-over drug placebo trial.

At present regular frequent monitoring of thyroid status is recommended for individuals with asymptomatic subclinical hypothyroidism but a trial period of thyroxine hormone therapy should be considered for symptomatic cases or those who have positive thyroid peroxidase antibodies.

iv) Screening

As clinical detection of a thyroid disorders (especially hypothyroidism) in patients with Down syndrome remains difficult (Mani, 1988; Prasher, 1995), regular thyroid function screening should be performed in all age groups of persons with Down syndrome.

Due to the general absence of incidence and long-term follow-up studies of thyroid disorders in the Down syndrome population the following recommendations are made for screening:-

1. Normal thyroid status-repeat tests every two years
2. Definite hypothyroidism-immediate thyroxine replacement therapy
3. Subclinical hypothyroidism-repeat tests every year
4. Definite hyperthyroidism-refer for medical opinion
5. Previous treatment-monitor yearly basis

Whether parents and siblings of a child with Down syndrome should also be assessed for thyroid disorders remains speculative. As the Down syndrome population continues to grow greater awareness amongst carers and professionals is required. With the advent of community care the importance of early detection of thyroid disorders needs to be particularly understood by general practitioners (Cumella et al 1992).

Conclusions

The association between Down syndrome and thyroid disorders is of both academic and clinical importance. There is a high prevalence of thyroid disorders; hypothyroidism commoner than hyperthyroidism, both congenital and acquired, more frequent in females than males and increasing with age. A"high index of suspicion" is required as the diagnosis of thyroid disorders in people with Down syndrome is difficult. Presentation may be atypical or may be associated with other medical conditions (premature puberty, diabetes mellitus, dementia). A number of immunological and genetic aspects still require further investigation. Management of thyroid disorders is similar to that in the general population but a greater emphasise on screening is required.

Correspondence

V. P. Prasher, Department of Psychiatry, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Mindelsohn Way, Edgbaston, Birmingham, England. B15 2QZ. (Tel: 0121 627 2831, Fax: 0121 627 2832, E-mail: vprasher@compuserve.com)

Acknowledgements

I would like to thank Professor J.A Corbett, Professor of Developmental Psychiatry, Dr D.J. Clarke, Senior Lecturer in Developmental Psychiatry and V.H.R Krishnan, Consultant Psychiatrist in Learning Disabilities with their help in writing earlier drafts of this manuscript.

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