Treatment Trial of Subclinical Hypothyroidism in Down Syndrome

The American Academy of Pediatrics (AAP) recommends yearly screening of thyroid studies in
DS. Clinical experience suggests that TSH concentrations in the subclinical hypothyroid range
(5-10 milli international units(mIU/L)) are not uncommon in DS, but the benefits and risks of
treating SCH in the DS population are not known. In adults, SCH has been associated with
increased cardiometabolic risk (CMR) and individuals with DS may be at increased
cardiometabolic risk as well.

Data in children with SCH are limited. Despite the recommendations to screen for thyroid
dysfunction, evidence to guide management of elevated TSH in children with DS is equally
sparse. In non-DS children, TSH>4.65 mIU/L was associated with lower HDL. One year of
levothyroxine treatment in short children with subclinical hypothyroidism and short stature
improved growth velocity. Left ventricular (LV) function and LV mass (by echocardiography)
was not different in 16 children with DS and subclinical hypothyroidism (TSH>6.5 mIU/L; mean
TSH = 7.8 mIU/L) vs. 25 children with DS and normal TSH. However, these findings may be
limited by the small sample size. An intervention study of 7 subjects age 2-42 years with DS
and hypothyroidism, defined as low T4 and normal or elevated TSH (0.2-18.9 mIU/L) on 8 weeks
of levothyroxine treatment did not improve developmental or functional outcomes.
Anthropometrics and CMR factors were not examined. In contrast, increased TSH in the absence
of overt congenital hypothyroidism is common in neonates with DS and prompted a randomized
controlled trial (RCT) in 181 neonates with DS. TSH-directed levothyroxine treatment was
associated with better growth, weight gain, and motor development after 24 months compared to
placebo. These findings highlight that the "asymptomatic" component of subclinical
hypothyroidism may have medically-relevant effects. This study will provide potentially
clinically relevant preliminary evidence for the treatment of subclinical hypothyroidism in
DS.

Inclusion Criteria:

- Males and females, ages 8 - 20 years

- Diagnosis of Down syndrome

- Subclinical hypothyroidism: TSH level between 5 - 10 mIU/L, normal T4

- Parental/guardian permission (informed consent) and if appropriate, child assent

- Females who are at least 11 years of age or who are menarchal must have a negative
urine/serum pregnancy test

- Committed to adherence to levothyroxine treatment and study completion

Exclusion Criteria:

- Pregnancy

- Type 1/Type 2 diabetes

- Chronic medical conditions or medication use that can affect growth, nutrition, blood
glucose, insulin secretion, or thyroid function (such as lithium or certain seizure
medications)

- Current use of levothyroxine or anti-thyroid hormone

- Cyanotic congenital heart disease, or pulmonary hypertension (as described by last
echo report in subjects with CHD), or congenital heart disease considered medically
unstable by the study cardiologists