THYROID DYSFUNCTION IN DOWN=92S = SYNDROME=20

Dr. = Sanjiv=20 Nanda

Deptt. of Pediatrics

Pt. B.D.S. PGIMS, = Rohtak

=20 Down Syndrome consists of a constellation of clinical signs and = symptoms=20 as well as biochemical, metabolic and endocrine dysfunctions with one = common=20 denominator in the form of three copies of the q22 band on long arm of=20 chromosome 21. Down Syndrome is the most common significant chromosomal = anomaly=20 in live births with an incidence of 1:800 live births. It is also the most common = genetic cause=20 of intellectual disability^1,2. Ninety five percent are due to = 21=20 trisomy as a result of meiotic =20 non-dysjunction, 4% due to a Robertsonian translocation where the = long=20 arm of chromosome 21 gets attached to the long arm of any of the = acrocentric=20 chromosomes 13/14/15 and 21, while 1% have a mosaic pattern³. = The=20 single most risk factor associated with Down Syndrome is increased = maternal age=20 at conception. Incidence in neonates born to mothers less than 25 years = age is 1=20 in 1400 live birth while that in mothers more than 45 years is 1 in 46 = live=20 births⁴. Advanced =20 paternal age has nto been shown to be a risk = factors^5,6. It is=20 however important to note that most children with Down Syndrome are born = to=20 mothers who are less than 30 years of age. This due to the more number = of=20 pregnancies in this age group as compared to those in women over 35 = years of=20 age.

=20 The various forms of thyroid dysfunction in Down Syndrome may be=20 congenital or acquired, compensated or uncompensated hypothyroidism, = transient=20 hypo or hyperthyroidism, or even persistent hypothroidism. A review of=20 literature shows that 3% to 54%^7,8,9 of older individuals = have biochemical evidence of = hypothyroidism.=20 The presence of antithyroid antibodies in Down Syndrome also varies from 13% to=20 40%^7,8,9.

=20 The clinical symptoms and signs of both Down Syndrome and hypothroidism are = overlapping to some extent e.g. hypotonia, lethargy, dullness, mental=20 retardation, growth failure, prolonged neonatal jaundice, delayed = closure of=20 fontanellae, macroglossia, obesity etc. The presence of undetected=20 hypothyroidism in a Downs=92 Child could compound the problems in an = already=20 compromised situation. The presence of other forms of thyroid = dysfunction in=20 Down Syndrome children could also put them at an increased health risks. = Hence=20 the need to study the thyroid dysfunctions in Down Syndrome.=20

MATERIALS AND=20 METHODS

=20 The study was carried out on all children who met the phenotypic = criteria=20 for establishing the diagnosis of Down =20 Syndrome and were attending Pediatrics Deptt., Postgraduate = Institute of=20 Medical Sciences Rohtak in both its outpatient department and indoors. = 32 Down=20 Syndrome cases aged less than/equal to 12 years were=20 studied.

=20 The eligibility inclusion criteria of the study included = patients diagnosed to be cases of Down = Syndrome=20 as suggested by mental retardation, brachycephaly, upslanted palpebral = fissures,=20 epicanthal fold, single simian crease, clinodactyly, short stature,=20 hypotonia macroglossia, = widely=20 spaced big and 2^nd toe, dermatoglyphics (ulnar loops, distal = triradil=20 single simian crease, = patter in=20 3^rd interdigital area (Fig.). A detailed record of the above = was made=20 in all patients of Down Syndrome. Patients who already were on thyroxine = or=20 antithyroid therapy were excluded. Down Syndrome patients in whom there = was a=20 family history of goitre, thyrotoxicosis, myxoedema or Hashimoto=92s = thyroiditis=20 were also excluded. =20

=20 They were looked for all clinical signs and symptoms of = hypothroidism or=20 hyperthyroidism, if any. =20 A detailed record of clinical spectrum of thyroid abnormalities, = if any,=20 was made. The = investigations=20 carried out in the subjects included : x-ray long bones for bone age, = X-ray=20 chest, complete haemogram, blood sugar, serum cholesterol, ultrasound of = thyroid, serum triiodothyronine (T₃), Thyroxine = (T₄),=20 thyroid stimulating hormone (TSH) levels. The technique of = radioimmunoassay was=20 adopted for the estimation of the thyroid hormones and thyrotropin = (Normal age=20 specific range were as per standard=20 guidelines)¹⁰.

=20 On the basis of above investigations patients were grouped as = euthyroid,=20 hyperthyroid, compensated hypothyroid or uncompensated hypothyroid.=20

RESULTS

=20 Twenty three patients were males, =20 while 9 were females. Mean of age was 3.3 years. Among features = possibly=20 attributable to hypothyroid, mental retardation and growth failure were=20 universally present in all the subjects. The mean developmental = coefficient was=20 49.5 (Mean DQ in Down Syndrome children in those with hypothyroidism was = 49.0=20 while in those without evidence of thyroid dysfunction as 52); hypotonia = (80%),=20 lethargy (53.1%), dullness (50%), macroglossia (65.5%) and decreased = appetite=20 (57.5%) were notably present. Two (62.5%) of the cases gave a history of = prolonged neonatal jaundice while delayed closure of fontanella was = found in=20 5(15.6%). None of the children had any true clinical evidence of=20 hyperthyroidism. The mean T3, T4 and TSH values were 138ng/ml, = 8.7microgram/ml=20 and 5.4 mU/L. Five (18.75%) children were found to have hypothyroidism = out of=20 which 4(12.5%) and compensated hypothyroidism i.e. raised TSH values in = the face=20 of normal T4 levels, while only one case was detected to be having = uncompensated=20 hypothyroidism.

=20 The ultrasonographic examination of the thyroid gland in all the = cases=20 were normal.

DISCUSSION=20

=20 The = present study was=20 undertaken to study the clinical spectrum of thyroid abnormalities and = thyroid=20 functions in Down Syndrome children aged less than 14 years.

=20 Among the features possibly attributable to hypothyroidism, = mental=20 retardation and growth failure were universally present in all the = subjects. The=20 presence of lower D.Q. or I.Q. is characteristic of both Down Syndrome = and=20 hypothyroidism . Mental retardation is universally present in patients = of Down=20 Syndrome as is observed in this study also.

=20 The cause of mental retardation in Down Syndrome children could = be due to=20 improper switching over of the fetal forms of insulin-like growth = factors=20 (IFG=92s) to the adult forms. These IGF=92s are produced endogenously in = the brain,=20 both growing and mature, and are responsible for brain growth and = myelination=20 and synaptogenesis independent of the action of growth hormone (GH).=20 Hypothyroidism causes delay in =20 synaptogenesis and myelination as well as decreases the brain = growth=20 potential, as it is the hormone responsible for maintaining the basic = metabolism=20 of all the tissues. As mental retardation is a common denominator to = both Down=20 Syndrome and hypothyroidsm, and both the conditions are known to = co-exist it=20 becomes important to screen the Down Syndrome children for hypothryoidsm = because=20 the co-existence of both the conditions would lead to further = developmental=20 retardation.

=20 The various forms of thyroid dysfunction in Down Syndrome may be=20 congenital or acquired, compared or decompensated hypothyroidsm, = transient hypo=20 or hyperthyroidism, or even persistent hypothyroidism. A review of = literature=20 shows that 3% to 54%^7,8,9 of older individuals have = biochemical=20 evidence of hypothyroidism. The results of this study is in concordance = with=20 those of the previous authors : to mention a few of them : Loudon et=20 al⁸ (1985) had observed a 30% prevalence of = sub-clinical/compensated=20 hypothyroidism in children with Down Syndrome. Lobo et al = (1975)¹¹=20 and Sare et al (1978)¹² =20 found an incidence of hypothyroidism in Down Syndrome children = less than=20 20 years to be 4% and 17% respectively.

=20 It seems that there is a wide variation in the data regarding the = prevalence of thyroid dysfunction among Down Syndrome patients. However = what is=20 clear from the review of literature available till date is that the = incidence of=20 congenital hypothyroidism in Down Syndrome cases is definitely higher = (30 times)=20 than that in the general population; the prevalence of 16.7% in the age = group=20 0-1 years in the present study could well be taken as a reflection of = the=20 prevalence of congenital hypothyroidism.

=20 That compensated hypothyroidism is the most prevalent form of = thyroid=20 dysfunction in Down Syndrome patient is also reflected from this study. = In the=20 present study five (18.75%) were found to have hypothyroidism out of = which=20 4(12.5%) were found to have compensated hypothyroidism i.e. raised TSH = values in=20 the face of normal T₄ levels, while only 1 (3.1%) was = detected to be=20 having uncompensated hypothyroidism.

=20 Hyperthyroidism was not observed in any of the cases included in = the=20 study. =20 Goitre is not a particular feature of thyroid disease in Down = Syndrome=20 None of the cases had any clinical or radiological (ultrasonography) = evidence of=20 enlarged thyroid gland.

=20 The mechanisms of = thyroid=20 dysfunction in Down Syndrome are unclear and many a hypothesis has been = put=20 forth. One such hypothesis put forth by Sharav et al (1988)¹³ = to=20 explain congenital hypothyroidism says it to be due to the immaturity of = the=20 hypothalamic pituitary-thyroid axis.⁹ This view is supported = by the=20 fact that delayed maturation of somatomedins in the form of incomplete = switching=20 over from foetal to adult forms¹⁴. Also observed is the = TSH insensitivity to TRH=20 stimulation¹⁵. This could result in the secretion of a thyrotropin of low biological = activity,=20 which, in turn, may be an expression of TRH deficiency^16,17. = The=20 other hypothalamic factors involved in TSH regulation, such as dopamine = or=20 somatostain levels may be involved. A mechanism of peripheral resistance = to=20 thyroid hormone has been = proposed=20 to explain the observation of isolated increased of TSH in the face of = normal=20 T₄ levels (compensated hypothyroidism). Supporting this view = is the=20 fact that the cell membranes in Down Syndrome are known to have abnormal = biochemical, physiological and receptor=20 functions^18,19.

=20 Clearly it is desirable to detect hypothyroidism in these = children who=20 already have growth retardation and learning disability. However = clinical=20 diagnosis of = hypothyroidism in Down Syndrome is difficult = since the=20 features are overlapping and symptoms such as weight gain, poor growth,=20 hypotonia and a dulling effect may be attributed to the syndrome itself. = This=20 highlights the importance of screening and biochemical confirmation of = the=20 diagnosis.

=20 Though treatment without clinical evidence of hypothyroidism has = not been=20 of much value, it has been shown beyond doubt that children with Down = Syndrome=20 below four years with elevated TSH levels had significant growth = retardation=20 compared to those with normal THS levels^18,20. Thyroxine=20 supplementation in infants with hypothyroidism and increased TSH and = exaggerated=20 TSH response to TRH led to increased growth during the period of = treatment.=20 Tuyuz B et al (2001)²¹ suggested that congenital = hypothyroidism=20 cases, especially those with TSH levels between 11 and 20 mU/L may = benefit from=20 low dose thyroxine=20 therapy.

BIBLIOGRAPHY

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3. = Hall=20 JG, Chromosmal clinical abnormalities, In : Behrman RE, Kliegman RM, = Jenson HB (eds)=20 : Nelson Textbook of Paediatrics 16^th ed. W.B. Saunders Co.,=20 Philadelphia 2000; 315-333.

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