Thyroid abnormalities in children with Down syndrome at St. Paul's hospital millennium medical college, Ethiopia

Abstract Background Subclinical hypothyroidism (SCH) is the commonest thyroid abnormality in patients with Down syndrome (DS). The purpose of this study was to determine the prevalence and types of thyroid abnormalities, to assess the age at diagnosis, and to examine the screening practice in children with DS in a resource limited setting. Methodology A retrospective study was conducted in children with DS seen at endocrine follow‐up clinic. Data were collected from patients' registration book and medical records. Result A total of 115 patients with DS were included in the study out of which 64 (59.8%) were males. Their median age at diagnosis was 9 months (range 4–15 years). Thyroid function test (TFT) was done at least once for 107 (93%) patients. Abnormal thyroid function was observed in 51 (47.7%) patients. The commonest thyroid abnormality was SCH (30/107, 28%) followed by congenital hypothyroidism (11/107, 10.3%), overt hypothyroidism (9/107, 8.4%) and hyperthyroidism (1/107, 0.9%). Most of the patients (86/107, 80.4%) were tested initially in the first 2 years of life. From those who were tested between the age of 2–6 months (n = 22 patients), seven (31.8%) patients had thyroid abnormalities. Conclusion Thyroid abnormalities were seen in a remarkable proportion of DS patients. The detection of abnormalities in the patients with age range of 2–6 months demands the need for additional TFT in this age category apart from the standard recommendation. Early diagnosis and management of thyroid abnormalities are important to decrease further impairment of cognition function in children with DS.

neurologic abnormalities, hematologic abnormalities and ophthalmic abnormalities. [4][5][6] Thyroid disorder is one of the abnormalities which can contribute to mental retardation in DS patients. 4 Depending on the definition of the thyroid abnormalities, the prevalence of thyroid dysfunction in children with DS ranges from 4% to 19.5%. [7][8][9][10] Its lifetime prevalence in DS is estimated to be 13%-63 %. 11,12 Thyroid dysfunction in DS can be autoimmune or non-autoimmune related. 6 From the autoimmune thyroid disease, Hashimoto's thyroiditis (HT) is more common than Graves' disease. HT might progress to Graves' disease (GD) more frequently in patients with DS than in the general population. 13,14 There are different forms of thyroid disorders. Congenital hypothyroidism (CH), subclinical hypothyroidism (SCH), overt hypothyroidism and hyperthyroidism. 15,16 From these, SCH is the most common form of thyroid abnormality reported in 25-32% of DS patients. 17,18 Non autoimmune SCH showed higher prevalence and earlier onset than autoimmune thyroiditis in children with DS which might be explained by congenital alteration in the regulation of thyroid gland which is directly related to the trisomy of chromosome 21. 19 Thyroid hormones are vital for the development of the central nervous system, particularly during infancy. 20 Failure of the thyroid gland to produce an adequate amount of thyroid hormones and delay in diagnosis of hypothyroidism in DS children will result in worsening of psychomotor development, somatic growth and mental retardation. 21,22 As the symptoms of hypothyroidism overlap with manifestations of DS, routine screening helps to pick thyroid function abnormalities earlier. In this regards, the American Academy of Pediatrics recommends thyroid function screening in children with DS at birth, 6 months, 12 months and yearly. 4 Therefore, screening for thyroid abnormalities at the recommended interval is crucial. 22 In many parts of the world, newborn screening for thyroid abnormalities is mandatory. 23 However, this is not a routine practice in developing countries like Ethiopia. Studies in DS patients were also very scarce in the developing countries. 24,25 The purpose of this study was to assess the prevalence and types of thyroid abnormalities in children with DS, to determine the age at diagnosis, and to evaluate thyroid function screening practice in children with DS in resource limited setting. were included in the study. Ethical approval was obtained from the institutional review board of SPHMMC. Patient information was anonymized and de-identified before analysis.

| ME THODOLOGY
Data on current age, sex, age at first thyroid function tests (TFT) determination, maternal age at conception, TFT (TSH and T4). For the TFT, 2-4 ml whole blood was taken using serum separator tube to analyse TSH and T4 using chemistry machine (Cobas 6000 analyser). Echocardiography and karyotyping results were retrieved from registration book and patient medical charts. The data were entered and analysed using SPSS Version 24. Continuous variables were categorized. Frequency tables and percentiles were used to describe variables. p-value < .05 was considered statistically significant.

| OPER ATIONAL DEFINITION
Phenotypic DS was defined as those patients diagnosed by the physical appearance of DS such as, low muscle tone, flat facial features, small nose, upward slanting of the eyes, epicantal fold, small abnormally shaped ears, simian crease, hyper flexibility, evidence of congenital heart disease and hypothyroidism. 1 Thyroid abnormality classification is indicated in Table 1.
Thyroid autoantibody tests and thyroid ultrasound were not done.

| RE SULTS
A total of 115 patients with DS were included in the study, out of which 64 (59.8%) were males and 51 (40.2%) were females. Their Subclinical hypothyroidism b "High" TSH with normal T4 at diagnosis Overt hypothyroidism b "High" TSH with low T4 at any time Hyperthyroidism b "LOW" TSH with high T4 level a High TSH (above 10 μIU/ml) or low T4 (below 10 μg/dl) in the new-born period. In this study new-born were tested between 7 days and 1 month of age. b Normal reference ranges for TFT beyond the neonatal period in the current study was as follows; for TSH 0.5-5 μIU/ml and for total T4 5.1-14 mcg/dl. The high and low cut-off points were based on established reference ranges. 37,38 and only one female patient had hyperthyroidism. The patient with hyperthyroidism was diagnosed at the age of 6 years ( Table 2).
In our study, out of the 22 DS patients who were screened between the ages of 2-6 months, 31.8% (7/22) had thyroid abnormalities as it was indicated in Table 3.
Boys were affected with thyroid abnormalities predominantly (33/51, 64.7%) than girls (18/51, 35.3%) but statistical difference was not observed in terms of mean TSH, T4 and types of thyroid abnormalities between the two groups.
We analysed the maternal age at conception, and we found more than half (62/115, 53.9%) of the mothers were older than 35 years of age when they got pregnant with these children (  Table 4.

| DISCUSS ION
DS is associated with several medical conditions and one of which is thyroid abnormalities. 5 There is a higher risk of thyroid function deterioration over time in patients with DS which seems to be related to higher baseline TSH levels at diagnosis and autoimmunity.
However, apart from overt hypothyroidism, SCH in DS appears to be unrelated to autoimmunity. 26 DS is usually associated with extrathyroidal autoimmunity than thyroid autoimmunity. 27 There is a wide range of prevalence of thyroid abnormalities in DS patients which can be explained by the variability in the definition of thyroid disorders, the different population size or the age of patients studied and by the different techniques used to measure the TFT in different studies. 11 In the current study, thyroid abnormalities were detected in 51 patients (47.7 %), which was higher than studies done in other countries like South Africa (34.5%), California (32.5%) and Oregon (24%). 6,22,25 Though, AAP recommends screening for thyroid abnormalities in DS patients at birth, 6 months, 12 months, and yearly then after, 4 in the present study, a significant number of thyroid abnormalities were detected between 2 and 6 months of age.
This might result in increased prevalence of thyroid abnormalities in the current study compared with the above studies. Other studies also recommend to have additional testing between 2 and 6 months of age. 6,22 Therefore, we propose additional screening in children with DS for thyroid abnormalities between 2 and 6 months of age in order to detect the abnormalities earlier and to start treatment timely.
In the current study, boys were affected with thyroid abnormalities predominantly than girls. But there was no statistically significant difference in the mean TSH and T4 between the two sexes unlike the general population where thyroid abnormality is common in girls than in boys. 30 The same finding was also seen in another study done in Oregon. 6 Advanced maternal age during conception is a risk factor for DS and other aneuploidy as a result of different speculated mechanisms such as recombination errors in the foetal stages of oogenesis, agerelated accumulation of damaged DNA and age-related hormonal variations which can increase the prevalence of aneuploidy in advanced age. 31 In this study, we found more than half of the mothers were older than 35 years of age when they got pregnant with these children substantiating association between older age and increased risk for DS. 31 SCH was the most common thyroid dysfunction seen in our study which is similar to previous studies done in South Africa,

TA B L E 2 Prevalence of different types of thyroid disease in DS patients at SPHMMC, Addis Ababa Ethiopia
Oregon and India. 6,25,32 Over expression of interferon which is found on chromosome 21 is one of the suggested mechanisms in causing SCH. 18 Thyroid autoimmunity is also another postulated cause of SCH. 10  were treated with levothyroxine as it is recommended in another study. 34 Despite the burden of both infectious and non-infectious diseases and inconsistent availability of TFT tests in Ethiopia, TFT was done for 93% of the patients, which was higher compared with another study done in South Africa (83.6%). 25 The eight patients who had no TFT determination were linked to the endocrine follow-up clinic from regular outpatient clinic for screening and follow-up but they did not show up.
In the current study, majority of patients were tested for thyroid function after the neonatal period. This might be the result of delayed diagnosis of DS because of lack of antenatal and newborn screening protocol in our setting. This calls for routine prenatal and neonatal screening of DS and thyroid disorders to avoid delay in diagnosis.
In our study, nine patients with hypothyroidism, both congenital and subclinical, which were not on therapy, had normal thyroid function on follow-up tests. All of them were below the age of one year. A similar finding was observed in a study done in Oregon 6 which can be explained by a temporary deficiency of thyroid hormone, which later recovers as a result of improved thyroxine production. 35 Based on this observation, we suggest follow-up TFT is important before initiating treatment at least for 6-8 months,

| CON CLUS ION AND RECOMMENDATIONS
In conclusion, thyroid abnormalities were seen in a high proportion of DS patients in our study which calls for placement of regular screening of patients with DS for thyroid abnormalities. The significant detection of abnormalities in the patients in age range of 2-6 months demands the need for additional TFT in this age range apart from the standard recommendation. Patients with DS should be screened also for other common co-morbidities and linked to respective referral clinics timely to decrease impairment of cognition and improve their quality of life.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

E TH I C A L A PPROVA L
The research got IRB approval from SPHMMC IRB.

CO N S E NT TO PU B LI S H
Not applicable.

DATA AVA I L A B I L I T Y S TAT E M E N T
All relevant data are available upon reasonable request.