Do Down Syndrome Babies Have Higher Incidence of Hypothyroidism

Background/Aims: Thyroid affliction is a common comorbidity in individuals with Down syndrome (DS), but historical studies have multiple limitations. We assessed thyroid abnormalities in a large cohort of children with DS. Methods: Retrospective records review from a single institution. Calculated prevalence of mutual thyroid abnormalities and associations with mutual comorbidities. Results: Amid 508 patients, 120 (24%) had a thyroid-related diagnosis, the majority having elevated thyrotropin treated with levothyroxine. A Kaplan-Meier estimate projects that 50% have thyroid disorder by adulthood, with xx% of hypothyroidism diagnosed earlier the age of 6 months. When tested, approximately 50% had positive antithyroid antibodies, though this rate was 100% in overt hypothyroidism. There was no association between congenital or acquired hypothyroidism and mutual comorbidities. Decision: Thyroid disease in DS is more mutual and occurs before than in the general population, and is often transient. Thyroid disease is unrelated to gender, obesity, or other comorbidities. Apart from overt hypothyroidism, much of hypothyroidism in DS appears unrelated to autoimmunity; we recommend checking of antithyroid antibodies just in select cases. An additional screen for thyroid disease between the newborn screen and the 6-calendar month well-child visit volition detect early cases of hypothyroidism who passed their newborn screen.

© 2017 S. Karger AG, Basel

Introduction

Down's syndrome (DS) is the most common autosomal aneuploidy with a national nascency prevalence of 14.57 per 10,000, or 1 in 691, live births [1]. Information technology is well established that patients with DS are at increased chance for the development of thyroid hormone abnormalities, with a reported prevalence between viii and 49%, depending on the definition of abnormality [two-xviii]. This includes all forms of thyroid affliction: congenital hypothyroidism; caused subclinical hypothyroidism; caused overt hypothyroidism; and hyperthyroidism. The broad range is due to pocket-size patient numbers in historical studies, and though some contempo studies have greater numbers, they lack diagnostic detail. Many studies also lack data related to possible associations of thyroid illness with other comorbidities, or were too small to reach statistical significance. The current American Academy of Pediatrics (AAP) guidelines on the intendance of patients with DS, based mainly on expert stance, recommend screening for thyroid dysfunction at nascency, six months, 12 months, and annually thereafter [nineteen]. The absence of a solid prove base has fabricated criteria for diagnosis and treatment decisions, in cases of subclinical hypothyroidism in particular, a hotly debated topic in the pediatric endocrinology literature.

The goals of this study are to better characterize the timing and prevalence of thyroid abnormalities in children with DS, to compare age at diagnosis between unlike types of thyroid illness, and to reexamine the screening recommendations. This study also investigates biochemical thyroid status, autoimmunity, treatment decisions, and possible related comorbidities. Of item interest was the evaluation of the prevailing wisdom that most thyroid diseases in DS are both permanent and related to autoimmunity [20].

Methods

The Child Development and Rehabilitation Heart at Oregon Health and Science University (OHSU) sees pediatric patients with DS primarily from Oregon and Washington in a multidisciplinary team setting. A retrospective review of the electronic medical tape (EMR) revealed 508 eligible patients seen in the DS clinic betwixt the dispensary opening in November 2007 through January 2015. L-seven additional patients with DS and a thyroid-related ICD-9 visit code were identified in the OHSU Pediatric Endocrine Clinic (PEC), though 2 were ultimately not diagnosed with thyroid disease. Data from PEC patients were added to DS dispensary data to increment power in clan analyses but were non used in prevalence calculations. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic tools hosted at the OHSU. REDCap is a secure, web-based application that supports data capture for enquiry studies, providing (1) interfaces for validated data entry; (2) inspect trails for tracking information manipulation and export procedures; and (3) automated export for data downloads. Approval for this report was obtained from the OHSU Institutional Review Board.

Demographic data included gender, ethnicity, and primary language at habitation. Ethnicity was determined by patient written report, was retrieved from the EMR, and was assessed in the study considering of possible differences in rates of autoimmunity or other comorbidities. Historic health data included karyotype, history and blazon of thyroid disease, age and thyroid function tests (TFTs) at the time of diagnosis, presence and type of antithyroid antibodies, treatment, history and blazon of cardiac disease and surgical interventions, and other notable comorbidities. Anthropometric data at visits included height, weight, and trunk mass index (BMI) as well as elevation, weight, and BMI percentiles for age. Height and weight percentiles were based on the DS growth charts from Cronk et al. [21]. BMI percentiles were based on Center for Disease Control growth charts for patients older than two years [22].

Thyroid illness was characterized as congenital hypothyroidism, subclinical hypothyroidism, overt hypothyroidism, isolated hyperthyrotropinemia, unknown hypothyroidism, and hyperthyroidism according to the criteria in Tabular array i as defined by the American Thyroid Association [23]. Although at that place potentially are differences in treatment practices with mildly elevated thyrotropin (TSH) levels, biochemical evidence of subclinical hypothyroidism was used to ascertain cases where available when handling was initiated by outside providers prior to evaluation in our clinics. To account for variability in handling practices, we have further separated cases of presumed subclinical hypothyroidism into those with TSH in a higher place the normal cutoff but below the commonly accepted treatment threshold of 10 μIU/mL and those with TSH greater than 10 μIU/mL. In cases where diagnostic data were unavailable, nomenclature was made based on abnormal TFTs, if available, within 6 months earlier starting treatment. All "unknown" patients on levothyroxine were counted among those with "acquired hypothyroidism" when applicable.

Table 1.

Diagnostic criteria for types of thyroid affliction

For comparisons between 2 groups, including percentage of patients tested for autoimmunity, percent of those testing positive, and differences in levothyroxine doses, a two-sided t test was used. Logistic regression was used to evaluate associations betwixt thyroid disease and age, gender, ethnicity, presence of cardiac affliction, BMI percentile, weight and weight percentile, and presence of gastrointestinal anomalies (Hirschsprung disease, duodenal atresia, and other gastrointestinal atresias). Because of collinearity, regression was repeated with cardiac surgery or cardiopulmonary bypass in place of cardiac disease. The Wald examination was used to compare individual variables for pregnant associations. Linear regression was used to evaluate differences in weight-based levothyroxine dose between subclinical and overt hypothyroidism. Within each subgroup, assay was done with χⁱⁱ comparison, except when groups were smaller than 5, in which case the Fisher exact test was used. All statistical analyses were performed using STATA 14.one software (StataCorp, College Station, TX, Us).

Results

Prevalence and Summary Statistics

V hundred and sixty-five patients were included in the study: 508 patients in the DS clinic and 57 patients in the PEC (Table 2). There was a slight male predominance (54%) and a high number of patients identified as Hispanic/Latino(a) (31%). The cohort is similar to published cohorts of patients with DS with regard to karyotype and common comorbidities (Table 1). Patients in the PEC were older and less probable to have a reported history of cardiac disease, though rates of cardiac surgery were not unlike between the clinics. The PEC had a higher percentage of patients with leukemia/myeloproliferative disease and type I diabetes.

Table two.

Demographics and comorbid diagnoses for children seen in the DS clinic (n = 508) and PEC (n = 57)

There were 422 patients without a thyroid-related diagnosis who had TSH and free thyroxine (FT4) recorded within 6 months of a visit, resulting in 648 TSH and FT4 measurements in total. This excludes any children diagnosed with thyroid disease based on TFTs at the visit in question. Mean TSH was 3.30 μIU/mL (range 0.04–ix.66). Mean FT4 was 1.04 ng/dL (range 0.6–2.0).

As shown in Tabular array 3, 120 (24%) patients in the DS clinic had a documented history of thyroid-related diagnosis: ii% congenital hypothyroidism, 10% subclinical hypothyroidism, 1% overt hypothyroidism, iv.5% with isolated hyperthyrotropinemia, four.iii% unknown hypothyroidism, and 1.6% hyperthyroidism. At that place was no difference in rates of any blazon of thyroid disease between males and females; mean serum TSH and FT4 at diagnosis are shown in Table 3. There was a statistically significant difference in TSH and hateful FT4 between those with overt and subclinical hypothyroidism (p < 0.005). All those with hyperthyroidism were diagnosed with Graves disease and treated with methimazole with skillful response to therapy.

Table iii.

Prevalence of different types of thyroid disease^a

For all patients, the median age at diagnosis with any thyroid affliction was 4 years and 10 months. For whatsoever acquired hypothyroidism, there was no statistical difference in age at diagnosis between those with subclinical and those with overt hypothyroidism. Amidst those diagnosed with hypothyroidism outside of newborn screening, 11 patients (7.5% of all acquired hypothyroidism) were diagnosed before the 6-calendar month screening recommended by the AAP, although indications for testing earlier were not determined. For hyperthyroidism, median age at diagnosis was just nether nine years. The odds of developing thyroid disease increased by ten% per year with increasing age. Using a Kaplan-Meier estimate for the evolution of thyroid disease, it is estimated that 25% of patients with DS will bear a diagnosis of thyroid dysfunction by age 7.five years and projected that up to fifty% will past the time they reach machismo (Fig. ane). This projection agrees with our clinical data, where at a hateful age of seven years at the fourth dimension of the visit 24% of the patients had thyroid affliction. When analysis is repeated and restricted only to patients with TSH >x μIU/mL at diagnosis, 25% of patients will take thyroid dysfunction by ten years of historic period, but 50% are still predicted to be afflicted by adulthood.

Fig. 1.

Kaplan-Meier bend showing the prevalence of whatever type of thyroid illness in the pediatric Downwards syndrome population.

Associations with Comorbidities

Logistic regression for the odds of developing any thyroid disease and congenital hypothyroidism or acquired hypothyroidism separately showed no relationship to gender, history of cardiac illness or cardiac surgery, demand for cardiopulmonary featherbed, BMI weight or height percentile, or presence of gastrointestinal anomalies. The absence of association held when looking at simply those with acquired hypothyroidism and TSH >x μIU/mL. There was an increased run a risk for thyroid disease in those with type I diabetes, though this was weighted to patients seen in the PEC.

Autoimmunity and Differences between Subclinical and Overt Hypothyroidism

A full of 99 patients had antithyroid antibodies tested, with 46 (46%) having any positive antibody (Tabular array four). Half of patients with positive antibodies had merely 1 antibody present and half-dozen (13%; all with hyperthyroidism) had more than 2. There were no differences in rates of antibody positivity between males and females (χ² exam, p = 0.2). Of those with diagnosis of acquired hypothyroidism, 62 had antibodies tested and 29 (47%) were positive. It was unclear in EMR documentation whether antibody positivity impacted diagnostic decisions. Of those with positive antibodies, fifteen/29 with acquired hypothyroidism and 7/15 with hyperthyroidism developed antibody positivity earlier the age of viii years, including 2 patients with anti-thyroperoxidase (antiTPO) antibodies detected at x and fourteen months, respectively.

Table 4.

Rates of antithyroid antibiotic testing and antibiotic positivity by diagnosis

Patients were equally likely to be tested for antibodies across all forms of acquired hypothyroidism. However, amongst those tested, patients with overt hypothyroidism and those with TSH >10 μIU/mL were more likely to exist antibiotic positive. For the population without thyroid dysfunction, 22 were tested for antithyroid antibodies with just 2/22 having any positive test.

Thyroid Hormone Dosing

Patients with TSH >11 μIU/mL appeared to require a 0.v mg/kg/day higher dose of levothyroxine when controlling for gender, age, and weight (95% CI 0.two–0.eight mg/kg, p = 0.001).

Transient Cases

Of note, 18 patients with a diagnosis of hypothyroidism (1/14 congenital, 10/76 subclinical, 4/28 isolated hyperthyrotropinemia, and 3/32 unknown) were not on therapy and had normal TSH and FT4 at their virtually recent screening. There was ane case of remission in the patients diagnosed with Graves disease. There were no pregnant differences in rates of nontreatment between diagnoses. The highest recorded diagnostic TSH for all transient cases was 13.6 μIU/mL. Almost half (8/eighteen) were diagnosed at or before the age of 3 years. Of these, four had measurements of antithyroid antibodies in the EMR, with 2 having positive antibodies. For those diagnosed after the historic period of 3 years, 5/6 tested had positive antibodies. Every bit a sensitivity analysis, repeat analyses of differences in antibody testing and positivity betwixt types of hypothyroidism, as discussed above, did not change conclusions when excluding those with transient hypothyroidism.

Give-and-take

Prevalence and Summary Statistics

This study confirms the previously reported loftier prevalence of thyroid disease in patients with DS. The majority of our patients accept mild, subclinical hypothyroidism or hyperthyrotropinemia without measurement of FT4. Unlike the general population, there is no female predominance for whatever type of thyroid disorder, including hyperthyroidism. When looking at all types of thyroid disease, both treated and untreated, up to 50% of patients with DS are expected to have a diagnosis of thyroid affliction by machismo.

Our report appears to ostend a relatively high prevalence of congenital hypothyroidism in children with DS. All patients were diagnosed by newborn screen, almost oft with a chief total T4 of less than the 10th percentile and elevated TSH [24]. The bulk of these cases are presumed to be permanent. The prevalence in the DS dispensary population of ane: 50 (two%), as shown in Table 3, is like to rates seen in other studies [3, 6, 25]. TSH by newborn screen blood spot was available for 8/14 and suggested milder disease with only moderately elevated TSH, though all only ane were still on levothyroxine replacement at a mean age of vi years at follow-upward. Although an association between congenital hypothyroidism and gastrointestinal anomalies has been suggested previously, in this larger study, no patients with congenital hypothyroidism had duodenal atresia, anal atresia, or Hirschsprung disease [three, 26].

The loftier rate of diagnosis after newborn screen but before the age of 6 months suggests a nonimmune thyroid dysfunction in infancy. This early dysfunction is too supported past the finding that more than half of patients diagnosed with hypothyroidism are diagnosed before the age of 5 years. This early dysfunction could be a mild form of congenital hypothyroidism that escapes detection past newborn screen, every bit suggested in before, smaller studies, though more conclusive studies would exist needed to confirm this hypothesis [25, 27]. In built hypothyroidism, information technology is well established that every calendar month without thyroid hormone supplementation worsens developmental outcomes at school age [28, 29]. If an additional screening for hypothyroidism were added at the routine well-child visits at 6–eight weeks and at four months for children with DS, this could better the developmental trajectory of some patients without adding additional physician visits for the family.

Autoimmunity and Differences betwixt Subclinical and Overt Hypothyroidism

Rates of autoimmunity in those without thyroid disease, as indicated by antithyroid antibody positivity, were lower than previously reported. This may exist sampling bias as those with pocket-sized abnormalities in TFTs may have been more likely to be labeled as hypothyroid if they had positive antibodies. Rates of positivity in our written report population for antiTPO were much college than for antithyroglobulin. In the general population, antibody positivity for either is approximately 10%, though antiTPO is more probable to be associated with biochemical thyroid affliction [30]. Although a previous report showed no cases of antibody positivity in early childhood in DS, we found that almost half of patients with positive antibodies developed them before the age of eight years [8]. There was also no departure in antibody positivity between males and females. When sorted by degree of TSH elevation or FT4 depression, antibody positivity did not bear upon levothyroxine requirements, though higher diagnostic TSH seemed to be associated with antibody positivity and all patients with depression FT4 had evidence of autoimmunity when measured.

Some authors have argued that patients with DS have a nonpathological shift in the normal range of TSH and that perhaps this leads to overdiagnosis of subclinical hypothyroidism [31, 32]. Indeed, Meyerovich et al. [32] reported a normal TSH reference range for good for you patients with DS to be 1.5–eight.9 μIU/mL. Our data showed a lower upper limit of normal with 2.5 standard deviations above the mean for TSH of vii.1 μIU/mL. Diagnostic TSH in subclinical hypothyroidism overlapped with this range merely mean TSH was college in those labeled equally having hypothyroidism. However, even in cases where TSH was clearly elevated, FT4 was maintained in the normal range in all just 9 of 83 patients in whom it was measured. TSH besides did not appear to exist greatly affected by obesity every bit seen in the general population [33]. When tested, much of subclinical hypothyroidism does non appear to exist autoimmune mediated, though the rates of antibody positivity are higher in all groups than reported for the US healthy adult population [30].

Transient Cases

Xiii percent of patients with a history of hypothyroidism were not receiving handling and had normal TFTs, despite high rates of antibody positivity when tested. Similar high rates of normalization of TSH peak are also found in the general population and take been reported in those with DS, though typically associated with absence of autoimmune illness [34, 35]. In congenital hypothyroidism, the disease is also more likely to exist transient in patients with DS [36]. Combined, these factors advise that TSH elevation may be transient in a significant portion of patients including those diagnosed in the starting time year of life. Patients may be mislabeled as having permanent hypothyroidism and volition be field of study to more frequent laboratory testing and physician follow-upwardly.

It has been suggested in 1 randomized controlled trial of patients with DS that treatment in the first 2 years of life results in small benefits in growth and gross motor development at 24 months, only there was no difference at follow-upwards at the age of ten years [37, 38]. The idea that there could be benefit and little impairment may result in physicians being more likely in this vulnerable population to treat transient TSH elevations without waiting for a confirmatory second test. This bias towards treatment increases the rate of recorded diagnoses of thyroid affliction in the DS population. The interpretation becomes self-perpetuating and is flawed, as the increased rate of diagnosis is likely due to the application of a different diagnostic treatment threshold compared to the full general population rather than a true departure in disease rates. We posit that this greater likelihood of diagnosing a normal patient with thyroid disease may exist mitigated by delaying diagnosis of subclinical hypothyroidism until more than 1 sample over two–3 months suggests sustained TSH elevation, though greater caution and clinical judgement may be required in children under the age of iii years.

There are multiple limitations to the electric current written report. All patients were seen in specialty clinics that potentially describe more than complex patients, although rates of common comorbidities were similar to other published cohorts [11, 12]. Diagnosis of thyroid disease was fabricated by outside providers in most cases, including decisions regarding interpretation of TFTs. Results for TSH and FT4 came from multiple institutions. Although there was a broad overlap between the normal ranges from different laboratories, the reported means should be interpreted with circumspection as laboratories do non share the same reference standards. In that location was a moderate amount of missing diagnostic information including TFTs for the 32 patients classified as "unknown hypothyroidism." Finally, a relatively small number of patients were screened for antithyroid antibodies, specially among those labeled equally not having thyroid affliction.

Conclusion

We believe our data support the decision that high rates of hypothyroidism are evidence of inherent dysfunction of the thyroid axis in patients with DS. Given the significant number of patients diagnosed before the age of 6 months, we recommend additional screening of TSH and FT4 betwixt newborn screening and the currently recommended 6-month screen (due east.g., around 2–iii months of age), though a further written report is warranted to determine the optimal timing for this test. While patients would otherwise exist detected at the currently recommended 6-month screen, with these boosted tests most, if non all, patients, with early hypothyroidism not detected on newborn screen would be started on critical therapy earlier. Approximately 100 patients would demand to be screened to find 1 case of infantile hypothyroidism. Although compliance with routine screening is low, the additional points of testing could theoretically meliorate rates of whatever testing being done in the showtime year [10].

We besides encourage recognition that all hypothyroidism is potentially transient. Peculiarly in patients diagnosed before the age of 3 years, we recommend direction similar to that for built hypothyroidism: consideration of a structured trial off therapy with recheck of TSH and FT4 in iv weeks in patients who have non had a rise in TSH >x μIU/mL on treatment nor required increases in levothyroxine dose after initiation of therapy [24, 39].

It would appear that most, if not all, cases of astringent hypothyroidism with low FT4 and cases of hyperthyroidism are secondary to autoimmune thyroid affliction. Nevertheless, prove of autoimmunity was not predictive of thyroid disease severity in the absence of meaning elevations in TSH and may not exist useful in the diagnosis of caused hypothyroidism in DS in cases with a single test showing balmy TSH elevation. We recommend testing only in cases where this would assist in decisions regarding treatment, with the caveat that fifty-fifty cases with positive antithyroid antibodies may take transient disease. Repeat testing of TSH and FT4 in two–3 months should be considered before a decision is fabricated to treat what could be a transient biochemical finding.

Acknowledgements

Salary support was given for M. Pierce provided in role by the National Institutes of Health Training Grant T32HD007497. REDCap Database was managed by the Oregon Clinical and Translational Research Found and supported by the National Eye for Advancing Translational Science of National Institutes of Health nether grant 1 UL1 RR024140 01.

The authors have no financial relationships relevant to this article to disclose. The authors have no conflicts of interest to this article to disclose.

The authors would similar to acknowledge Daniel Pinter for aid with data collection and Katrina Ramsey, MPH for advice on statistical analysis. Ms. Ramsey is supported past the Oregon Clinical and Translational Inquiry Institute, with funding by the National Center for Advancing Translational Scientific discipline of National Institutes of Health under grant 1 UL1 RR024140 01.

Author Contributions

Dr. Pierce conceptualized and designed the study and data collection instruments, performed data collection, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Pierce had full access to all the information in the study and takes responsibility for the integrity of the data and the accurateness of the data assay. Dr. LaFranchi provided disquisitional feedback in the development of the report, reviewed and revised the manuscript, and canonical the final manuscript equally submitted. Dr. Pinter assisted with the conceptualization and pattern of the report, reviewed and revised the manuscript, and approved the terminal manuscript equally submitted.

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