Elsayed, S M

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The Egyptian Journal of Medical Human Genetics (2014) 15, 407–408HO ST E D  BYAin Shams UniversityThe Egyptian Journal of Medical Human Geneticswww.ejmhg.eg.netwww.sciencedirect.comEDITORIALSubclinical hypothyroidism in childrenwith Down syndrome: To treat or not to treat???Peer review under responsibility of Ain Shams University.http://dx.doi.org/10.1016/j.ejmhg.2014.08.0031110-8630  2014 Production and hosting by Elsevier B.V. on behalf of Ain Shams University.Congenital hypothyroidism is 30 times more frequent innewborns with Down syndrome (DS) than in the populationof healthy children [1]. Mild isolated plasma thyrotropin(TSH) elevation with normal thyroxine (T4) levels is the mostcommonly seen pattern of thyroid dysfunction in these chil-dren [2,3]. Other terminology used for this pattern of abnor-mality includes isolated hyperthyrotropinemia, compensatedhypothyroidism, and subclinical hypothyroidism [4,5]. Theprevalence of mild TSH elevation (4–10 mIU/l) is estimatedat 80–90% in early infancy and 30–50% thereafter [3].The cause of neonatal hypothyroidism in this particularsyndrome remains unclear; most patients have normal thyroidscans excluding thyroid agenesis or ectopic thyroid tissue. Theabsence of goiter suggests that it is not caused by dyshormono-genesis [6,7]. Some authors suggested that it could be due to adelay in the maturation of the hypothalamic-pituitary-thyroidaxis [8]. Others postulated that infants with transient TSH ele-vation have a higher incidence of congenital malformationsthan infants with permanent congenital hypothyroidism [9].So, it may be hypothesized that newborns with congenital mal-formations similar to DS suffer perinatal stress, which maylead to TSH elevation [10].Other possible explanations include an inappropriaterelease of TSH related to a central disorder, the productionof a less active form of TSH, or some form of TSH insensitivityin the thyroid gland [11].The issue whether treatment of this mild form of subclinicalhypothyroidism is beneficial to children with DS is still contro-versial especially that this particular type of thyroid dysfunc-tion is self-limiting and high TSH tends to normalizespontaneously in most of the DS patients [11]. Keeping in mindthat elevated TSH levels in early life cannot predict the develop-ment of manifest thyroid disease later in childhood [12].It is known that mild thyroid insufficiency may diminish tis-sue sensitivity to growth hormone in normal children [13]. Thesame occurs in children with DS. Sharav et al. reported thatgrowth in DS children with a TSH value >5.7 mIU/l was par-ticularly retarded in comparison to the general population ofchildren [14].On the other hand, Selikowitz annually assessed the healthcondition of 101 children with DS. No significant differences ingrowth and development between those with subclinical hypo-thyroidism and those with normal thyroid function wererevealed [15]. Also, Gruneiro de Papendieck et al. did notnotice a significant difference in height SDS between groupsof children with TSH levels below and above 5 mIU/l [16].Later, a randomized double-blind 24-month trial compris-ing 196 DS neonates with subclinical or overt hypothyroidismwas found to have a statistically significant difference in lengthand weight gains between treated and placebo groups [17].This was further supported by Kowalczyk et al. [18] workwhich showed that early administration of L-thyroxin DSchildren with subclinical or overt hypothyroidism results in asignificant improvement in the growth of these children [18].Not only their physical growth but they also noticed a signif-icant improvement in their psychomotor development [18].Moreover, subclinical hypothyroidism may also signifi-cantly increase hypotonia and anemia in these children [19].Subclinical hypothyroidism has also been associated withhypercholesterolemia atherosclerosis and eventually coronaryheart disease particularly in those with a TSH concentration of10 mIU/L or greater [20,21]. Moreover, subclinical hypothy-roidism increases arterial stiffness anddiastolic dysfunction [22].It has long been known that DS patients have higher cho-lesterol levels [23] and recently they were found to have a sig-nificantly higher left ventricular diastolic dysfunction than thatobserved in the controls [24]. So not giving L-thyroxin to sub-clinical hypothyroidism in DS children would further increasetheir cholesterol level, diastolic dysfunction and their risk ofcoronary heart disease.In conclusion, subclinical hypothyroidism is the most com-mon thyroid dysfunction in DS. Although it is a self-limitingcondition, L-thyroxin administration will improve growth,hypotonia and psychomotor functions. It may also decreasethe risk of hypercholesterolemia, hypertension and eventuallycoronary heart disease in these children.References[1] Barg E, Chącka D, Komar A. Endocrinological disordersassociated with Down’s syndrome. Pediatr Pol 2006;81:844–9.[2] Rubello D, Pozzan GB, Casara D, Girelli ME, Boccato S, RigonF, Baccichetti C, Piccolo M, Betterle C, Busnardo B. Naturalcourse of subclinical hypothyroidism in Down’s syndrome:408 Editorialprospective study results and therapeutic considerations. J Endo-crinol Invest 1995;17:35–40.[3] Jiménez-López V, Arias A, Arata-Bellabarba G, Vivas E, DelgadoMC, Paoli M. Concentration of thyrotropic hormone and freethyroxin in children with Down’s syndrome. Invest Clin2001;42:123–30.[4] Fort P, Lifshitz F, Bellisario R, Davis J, Lanes R, Pugliese M,et al. Abnormalities of thyroid function in infants with Downsyndrome. J Pediatr 1984;104:545–9.[5] Pezullo JC, Jackson IM, Giesswein P, et al. Thyroid function inDown’s syndrome. Res Dev Disabil 1991;12:287–96.[6] Selikowitz M. A five year longitudinal study of thyroid function inchildren with Down’s syndrome. Dev Med Child Neurol1993;35:396–410.[7] Devos H, Rodd C, Gagne N, Laframboise R, Van Vliet G. Asearch for the possible molecular mechanisms of thyroid dysgen-esis: sex ratios and associated malformations. J Clin EndocrinolMetab 1999;84:2502–6.[8] Tüysüz B, Beker DB. Thyroid dysfunction in children withDown’s syndrome. Acta Paediatr 2001;90:1389–93.[9] Oakley GA, Muir T, Ray M, Girdwood RW, Kennedy R,Donaldson MD. Increased incidence of congenital malformationsin children with transient thyroid-stimulating hormone elevationon neonatal screening. J Pediatr 1998;132:726–30.[10] Cebeci AN, Güven A, Yıldız M. Profile of hypothyroidism inDown’s syndrome. J Clin Res Pediatr Endocrinol 2013;5:116–20.[11] Gibson PA, Newton RW, Selby K, Price DA, Leyland K,Addison GM. Longitudinal study of thyroid function in Down’ssyndrome in the first two decades. Arch Dis Child 2005;90:574–8.[12] Myrelid A, Jonsson B, Guthenberg C, von Döbeln U, Annerén G,Gustafsson J. Increased neonatal thyrotropin in Down syndrome.Acta Paediatr 2009;98:1010–3.[13] Susperreguy S, Muñoz L, Tkalenko NY, Mascanfroni ID,Alamino VA, Montesinos MM, Masini-Repiso AM, Miras MB,Pellizas CG. Growth hormone treatment in children withidiopathic short stature: correlation of growth response withperipheral thyroid hormone action. Clin Endocrinol (Oxf)2011;74:346–53.[14] Sharav T, Collins Jr RM, Baab PJ. Growth studies in infants andchildren with Down’s syndrome and elevated levels of thyrotro-pin. Am J Dis Child 1988;142:1302–6.[15] Selikowitz M. A five-year longitudinal study of thyroid function inchildren with Down syndrome. Dev Med Child Neurol1993;35:396–401.[16] Gruñeiro de Papendieck L, Chiesa A, Bastida MG, Alonso G,Finkielstain G, Heinrich JJ. Thyroid dysfunction and high thyroidstimulating hormone levels in children with Down’s syndrome. JPediatr Endocrinol Metab 2002;15:1543–8.[17] van Trotsenburg ASP, Vulsma T, van Rozenburg-Marres SL, vanBaar AL, Ridder JC, Heymans HS, et al. The effect of thyroxinetreatment started in the neonatal period on development andgrowth of two years old Down syndrome children: a randomizedclinical trial. J Clin Endocrinol Metab 2005;90:3304–31.[18] Kowalczyk1 K, Pukajo1 K, Malczewska1 A, Król-Chwastek1 A,Barg E. L-thyroxine therapy and growth processes in childrenwith Down syndrome. Adv Clin Exp Med 2013;22:85–92.[19] Lebel EW, Tenenbaum A, Malkiel S, Kastiel Y, Abu-Libdeh A,Zangen D. Low-normal FT4 and subclinical hypothyroidism mayhave a detrimental clinical effect in Down syndrome. Horm ResPaediatr 2011;76(Suppl. 2):46–7.[20] Biondi B, Cooper DS. The clinical significance of subclinicalthyroid dysfunction. Endocr Rev 2008;29:76–131.[21] Hak AE, Pols HA, Visser TJ, et al. Subclinical hypothyroidism isan independent risk factor for atherosclerosis and myocardialinfarction in elderly women. Ann Intern Med 2000;132:270–8.[22] Masaki M, Komamura K, Goda A, Hirotani S, Otsuka M,Nakabo A, et al. Elevated arterial stiffness and diastolic dys-function in subclinical hypothyroidism. Circ J 2014;78:1494–500.[23] Zamorano A, Guzmán M, Aspillaga M, Avendaño A, Gatica M.Concentrations of serum lipids in children with Down’s syndrome.Arch Biol Med Exp (Santiago) 1991;24:49–55.[24] Al-Biltagi M, Serag AR, Hefidah MM, Mabrouk MM. Evalua-tion of cardiac functions with Doppler echocardiography inchildren with Down syndrome and anatomically normal heart.Cardiol Young 2013;23:174–80.Solaf M. Elsayed *Genetics Unit, Children’s Hospital, Ain Shams University,Cairo, Egypt*Address: Medical Genetics Center, 27 A Baghdad St. Korba,Cairo, Egypt. Tel.: +202 24151999; fax: +202 24150977.E-mail address: elsayed683@yahoo.comAvailable online 16 September 2014

Editorial: Subclinical hypothyroidism in children with Down syndrome: To treat or not to treat???

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Editorial: Subclinical hypothyroidism in children with Down syndrome: To treat or not to treat???

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