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Vol. 78, No. 2, 2012
Issue release date: September 2012
Horm Res Paediatr 2012;78:113–118

Euthyroid Submedian Free T4 and Subclinical Hypothyroidism May Have a Detrimental Clinical Effect in Down Syndrome

Tenenbaum A. · Lebel E. · Malkiel S. · Kastiel Y. · Abulibdeh A. · Zangen D.H.
aDepartment of Pediatrics Hadassah Mt. Scopus and bDivision of Pediatric Endocrinology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Background: Aberrant thyroid function is highly prevalent in Down syndrome (DS). We aimed to find whether subclinical hypothyroidism (SCH) or low-normal free T4 (FT4) are associated with a detrimental clinical outcome in untreated DS patients. Methods: 157 patients assessed at Hadassah Down Syndrome Center between 2004 and 2010 by comprehensive clinical evaluation and tests for hemoglobin, FT4 and thyroid-stimulating hormone (TSH) were subdivided into subgroups including: clinical hypothyroidism, SCH, euthyroid submedian or supramedian FT4, and alternatively for euthyroidism and TSH levels (submedian or supramedian TSH). Results: Hypothyroidism was found in 21.7% and SCH in another 14.9% of the patients. Moderate/severe hypotonia were more frequent among SCH patients compared to euthyroid patients (52.6 vs. 16.4%, p = 0.002). Patient’s hemoglobin levels were lower in the euthyroid submedian FT4 group compared to the euthyroid supramedian FT4 group (10.9 vs. 0% below the normal range, p = 0.001). Interestingly, FT4 levels correlated negatively with increasing age among euthyroid DS patients (Pearson’s correlation coefficient = –0.324, p = 0.009). Conclusion: SCH and euthyroid submedian FT4 may have significant clinical sequelae, such as hypotonia and anemia. Interventional studies with l-thyroxine replacement may be indicated in these subpopulations. Our finding that FT4 levels decrease with age in DS (contrasting the general population trend) may indicate redefining the normal FT4 levels range in DS.

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  1. Nancy J, Roizen NJ, Patterson D: Down’s syndrome. Lancet 2003;361:1281–1289.
  2. Kennedy RL, Jones TH, Cuckle HS: Down’s syndrome and the thyroid. Clin Endocrinol 1992;37:471–476.
  3. Karlsson B, Gustafsson J, Hedov G, Ivarsson SA, Anneren G: Thyroid dysfunction in Down’s syndrome: relation to age and thyroid autoimmunity. Arch Dis child 1998;79:242–245.
  4. American Academy of Pediatrics: Health supervision for children with Down syndrome. Pediatrics 2001;107:442–449.

    External Resources

  5. Kliegman RM, Behrman RE, Jenson HB, Stanton BF: Nelson Textbook of Pediatrics, ed 18. Saunders, Philadelphia, 2007, pp 507–509, 2319–2327, 2944–2949.
  6. Benda CE: Down’s Syndrome – Mongolism and Its Management. New York, Grune & Stratton, 1969, pp 81–82, 166–176, 239–242.
  7. van Trotsenburg AS, Vulsma T, van Santen HM, Cheung W, de Vijlder JJ: Lower neonatal screening thyroxine concentrations in Down syndrome newborns. J Clin Endocrinol Metab 2003;88:1512–1515.
  8. Sharav T, Collins RM Jr, Baab PJ: Growth studies in infants and children with Down’s syndrome and elevated levels of thyrotropin. Am J Dis Child 1988;142:1302–1306.
  9. Jimenez-Lopez V, Arias A, Arata-Bellabarba G, Vivas E, Delgado MC, Paoli M: Concentration of thyrotropic hormone and free thyroxin in children with Down’s syndrome. Invest Clin 2001;42:123–130.
  10. van Trotsenburg AS, Kempers MJ, Endert E, Tijssen JG, de Vijlder JJ, Vulsma T: Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 2006;16:671–680.
  11. Biondi B, Cooper DS: The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76–131.
  12. Rubello D, Pozzan GB, Casara D, Girelli ME, Boccato S, Rigon F, Baccicheti C, Piccolo M, Betterle C, Busnardo B: Natural course of subclinical hypothyroidism in Down’s syndrome: prospective study results and therapeutic considerations. J Endocrinol Invest 1995;18:35–40.
  13. Prasher V, Gomez G: Natural history of thyroid function in adults with Down syndrome – 10-year follow-up study. J intellect Disabil Res 2007;51:312–317.
  14. Pueschel SM, Pezzullo JC: Thyroid dysfunction in Down syndrome. Am J Dis Child 1985;139:636–639.
  15. Toscano E, Pacileo G, Limongelli G, Verrengia M, Di Mita O, Di Maio S, Salerno M, Del Giudice E, Caniello B, Calabro R, Andria G: Subclinical hypothyroidism and Down’s syndrome; studies on myocardial structure and function. Arch Dis Child 2003;88:1005–1008.
  16. Selikowitz M: A five-year longitudinal study of thyroid function in children with Down syndrome. Dev Med Child Neurol 1993;35:396–401.
  17. Tirosh E, Taub Y, Scher A: Short-term efficacy of thyroid hormone supplementation for patients with Down syndrome and low borderline thyroid function. Am J Ment Retard 1989;93:652–656.
  18. van Trotsenburg AS, Vulsma T, van Rozenburg-Marres SL, van Baar AL, Ridder JC, Heymans HS, Tijssen JG, de Vijlder JJ: The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metab 2005;90:3304–3311.
  19. Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB: Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988;81:102–110.
  20. CDC – Centers for Disease Control and Prevention: BMI Percentile Calculator for Child and Teen. (accessed May 5, 2009).
  21. Nichols Institute Diagnostics, San Juan Capistrano, CA 92675. Cited at Nelson Textbook of Pediatrics, ed 18. Philadelphia, Saunders, 2007, p 2949.
  22. Esoterix Endocrinology, Calabasas Hills, CA 91301. Cited at Nelson Textbook of Pediatrics, ed 18. Philadelphia, Saunders, 2007, p 2949.
  23. Mehmet E, Aybike K, Ganidagli S, Mustafa K: Characteristics of anemia in subclinical and overt hypothyroid patients. Endocr J 2012;59:213–220.
  24. Tenenbaum A, Malkiel S, Wexler ID, Levy-Khademi F, Revel-Vilk S, Stepensky P: Anemia in children with Down syndrome. Int J Pediatr 2011;2011:813541.
  25. Elmlinger MW, Kuhnel W, Lambrecht HG, Ranke MB: Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine-binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med 2001;39:973–979.
  26. Hubner U, Englisch C, Werkmann H, Butz H, Georgs T, Zabransky S, Herrmann W: Continuous age-dependent reference ranges for thyroid hormones in neonates, infants, children and adolescents established using the ADVIA Centaur Analyzer. Clin Chem Lab Med 2002;40:1040–1047.
  27. Djemli A, Van Vliet G, Belgoudi J, Lambert M, Delvin EE: Reference intervals for free thyroxine, total triiodothyronine, thyrotropin and thyroglobulin for Quebec newborns, children and teenagers. Clin Biochem 2004;37:328–330.
  28. Kapelari K, Kirchlechner C, Hogler W, Schweitzer K, Virgolini I, Moncayo R: Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord 2008;8:15.

    External Resources

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