Abstract
We describe seven infants with transient congenital hypothyroidism (CH) due to maternal thyroid-stimulating hormone receptor (TSH-R) blocking antibodies (TRAb) identified over three decades of newborn screening for CH in Wales, UK that represents a minimum incidence of 1.6% of CH cases. Infants with transient CH due to maternal TRAb presented with a spectrum of clinical and biochemical hypothyroidism. Blood spot TSH concentrations ranged 60.5–332 mIU/L. CH was confirmed by plasma thyroid function tests in all cases (plasma TSH ranged 21–752 mIU/L). The seven infants belonged to five different families. On examination, four infants were clinically hypothyroid. Five infants had a thyroid ultrasound, of which three were abnormal. All infants were treated with thyroxine, which was subsequently withdrawn from three. Following thyroxine withdrawal, one infant resumed normal thyroid function and two developed compensated hypothyroidism. Of the five mothers, two had undiagnosed hypothyroidism and three were receiving thyroxine for longstanding hypothyroidism. Thyroid peroxidase antibody (aTPO) was measured in four and was negative in two, borderline positive in one and strongly positive in another. TRAb was measured in all five women and was strongly positive in all of them. This case series highlights the importance of identifying CH due to TRAb by investigating both the infant and the mother following a raised TSH found on newborn screening. The identification of those infants with transient CH caused by maternal transfer of TRAb is essential for optimizing management during childhood (including potential withdrawal of thyroxine replacement in the longer term) and in any subsequent pregnancy.
Introduction
In the UK, infants are screened for congenital hypothyroidism (CH) using blood spot thyroid-stimulating hormone (TSH) at days 5–8 of life. 1 CH may be permanent, due to thyroid gland agenesis, dysgenesis or ectopia or dyshormonogenesis, or it may be transient. Transient forms of CH may be due to exposure to maternal thyrotropin receptor antibodies (TRAb), antithyroid drugs, iodine excess or iodine deficiency. 2 Distinguishing between permanent and transient forms of CH at the time of diagnosis is difficult. Since there is a sense of urgency to treat CH once the diagnosis is made to prevent any long-term neurological sequelae, a clinical decision is usually taken to start replacement therapy with thyroxine. CH is usually permanent if the isotope uptake scan or thyroid ultrasound scan (US) reveals an ectopic or absent thyroid gland or if during the first two years of therapy, the baby requires increasing thyroxine replacement to maintain serum TSH concentrations within the reference range. If a permanent cause of CH has not been established, it is recommended to withdraw treatment at two–three years of age to assess requirement. 3 However, it is unclear as to how many infants identified through screening programs in the UK undergo this re-evaluation and have unequivocal permanent hypothyroidism. This information is also not systematically collected by screening programs in the USA. 2
Transient CH due to TRAb generally occurs in infants of mothers with a history of autoimmune hypothyroidism who are taking thyroxine or have undiagnosed hypothyroidism and has been reported to account for two percent of cases of CH in the USA. 4 TRAb are generally immunoglobulins of the gamma subtype (IgG) directed against the thyrotropin receptor 5 which cross the placenta from around 16 weeks of gestation onwards. 6 TSH regulates both the function and growth of the thyroid gland. 7 TRAb have a pathogenic role in the development of hypothyroidism in the mother and baby by blocking the effects of TSH. 6,8 Maternal TRAb gradually clear from the infant's circulation after 3–4 months and normal thyroid function resumes. Transient CH due to maternal TSH-R blocking antibodies can be confirmed by measurement of TRAb or thyroid receptor binding inhibitory antibodies (TBII) in the mother's serum. 9 Although thyroid peroxidase antibody (aTPO) is characteristic of autoimmune hypothyroidism, Brown et al. 4 have previously reported that in contrast to striking TSH-receptor blocking activity, detection of aTPO was variable in mothers of infants with transient CH.
Case series
During the period of 1982–2010, 966,969 infants were screened for CH in Wales. CH was identified in 375 infants (154 men and 221 women) that gives an incidence of 1:2579. Of the 375 cases of CH detected, six (1.6%) were found to have transient CH due to TRAb. However, we suspect that this is an underestimate of TRAb as a cause of CH in our population. Review of screening laboratory records for all infants with CH detected in Wales identified a further infant, from the early days of the screening program, with transient hypothyroidism born to a mother with a previous history of Graves' disease. We have not included this case in our series because TRAb were not measured and the diagnosis was not confirmed.
We describe a case series of seven infants with transient CH due to TRAb (six identified in Wales and a further case, a sibling of one of the six, screened elsewhere). By reviewing these cases we provide an insight into the importance of TSH signalling in normal growth of the thyroid gland in utero and the long-term clinical effect of blocking this pathway. We consider that this case series will also serve as a reminder to clinicians and scientists who may be involved in follow-up and confirmatory testing in infants with CH of the possibility of ‘transient’ CH due to maternal TRAb.
Biochemical investigations in the infants
Biochemical information on the infants is given in Table 1. The screening blood spot TSH in affected infants ranged from 60.5 to 332 mIU/L. Hypothyroidism was confirmed in all infants by plasma thyroid function tests. Plasma TSH ranged from 21 to 752 mIU/L. An absolute numerical value for plasma TSH was not available in two infants, whose TSH concentration was reported as greater than the working range of the assay. Three of the seven infants were clinically hypothyroid on examination and a fourth was reported to have prolonged jaundice (bilirubin 296 μmol/L). Thyroglobulin (Tg) was measured in five subjects with concentrations ranging from 11 to 215 μg/L, and was indicative of the presence of thyroid tissue in all cases.
Clinical and investigative data of seven infants with transient neonatal hypothyroidism due to TRAb
TRAb, TSH-R antibody; Tg, thyroglobulin; TSH, thyroid-stimulating hormone; US, ultrasound scan; TRH, thyrotropin-releasing hormone; FT4, free thyroxine
Blood spot TSH is the mean of duplicate TSH measurements on newborn screening. Blood spot TSH screen positive is >20 mU/L. Confirmatory plasma TFT includes TSH (mU/L), FT4 (pmol/L) and the age in days at which sample was taken (day of birth taken as day 0)
For cases 1 and 2, Tg was measured using the Pasteur Tg immunoradiometric assay. For cases 4, 6 and 7, Tg was measured using the Brahms Tg-PluS DYNOtest immunometric assay. Neonatal reference ranges for Tg using these methods are not available
Ultrasound and uptake scan
US data were available on four of seven infants (Table 1). Of these, three were found to have abnormalities, two with a small thyroid gland and another with one small thyroid lobe. Two of these three with abnormal US findings were siblings with particularly severe hypothyroidism, presenting with a plasma TSH concentrations of 752 and 506 mIU/L, respectively. Technetium uptake scan data were available for five of the seven cases (Table 1). There was no uptake in two of the cases. Again these were the siblings with the most severe hypothyroidism as judged by the initial blood spot TSH concentration. There was uptake in the neck of the remaining three infants.
Clinical course
In our case series, thyroxine was withdrawn from three of the seven infants. Thyroxine has not yet been withdrawn in two as they are currently under two years of age. A further infant remains on thyroxine without challenge because of the abnormality on US scan (case 3, Table 1). Normal thyroid function resumed in one of the three infants in whom thyroxine was withdrawn. Compensated hypothyroidism on withdrawal of thyroxine was found in the other two.
Biochemical investigations in the mothers
We have information on five mothers, two of whom have each had two affected infants (Table 2). Two of the five mothers were found to have undiagnosed hypothyroidism that was identified because of the investigations initiated on the finding of an increased blood spot TSH in their infants. Three of the five were on thyroxine for longstanding hypothyroidism.
Biochemical and clinical data on mothers of infants with transient neonatal hypothyroidism due to TRAb
TRAb, TSH-R antibody; aTPO, thyroid peroxidase antibody
In our data-set, aTPO was measured in four of the five mothers and was found to be absent in two, borderline positive in one and strongly positive in the fourth. Microsomal antibody was measured in one and was absent. TRAb or TBII was measured in four mothers and one infant and was positive in all of them. Our data confirm that maternal TRAb and not aTPO should be the test of choice.
Discussion
We describe seven cases of CH due to maternal TRAb, which demonstrate a wide spectrum of severity of clinical presentation and in whom starting thyroxine replacement without delay should be considered. This case series demonstrates that investigative tests such as maternal thyroid function tests and TRAb, and in the neonate, US and uptake scan imaging as well as systematic withdrawal of thyroxine in selected infants at age two–three years are of paramount importance in the elucidation of the cause of CH. Our data concur with that of Brown et al. 4 and confirm that maternal TRAb and not aTPO should be the test of choice. The measurement of maternal aTPO has no utility in the investigation of these patients.
The requirement for TRAb and not aTPO is not made clear in the UK Newborn Screening Program Centre standards for the initial clinical referral of infants with an increased blood spot TSH, which state that thyroid antibodies are desirable additional tests. 10 Most clinical biochemistry laboratories will interpret a request for thyroid antibodies as a request for aTPO as this is a more frequently requested test. The more recent UK Guidelines for the Use of Thyroid Function Tests 9 do address this point and specify that TRAb should be measured. The measurement of TRAb in infants at diagnosis can be problematic as high serum TSH concentration can interfere in the TRAb assay 11 and some assays are not suitable for use with lithium heparin plasma, 12 which is the sample of choice for most neonatal investigations including thyroid function tests. Hence, maternal serum is the sample of choice. The UK Newborn Screening Program Centre standards are currently under review and it is anticipated that these points will be incorporated.
Three of our cases had hypoplastic glands and two of these had compensated hypothyroidism on withdrawal of thyroxine. We have previously reported the small thyroid gland found in one of these siblings, 13 who had compensated hypothyroidism on withdrawal of thyroxine at 16 months of age. We postulated that the potent TRAb detected in his serum had disrupted the normal growth of the thyroid gland. The finding of small thyroid glands in two further affected children adds further evidence of the importance of TSH stimulation to thyroid growth in the neonatal period. In contrast, a report of 11 infants with transient neonatal hypothyroidism by Brown et al. 4 did not observe any infants with long-term abnormality in thyroid function. They postulated that this is consistent with the fact that TRAb, like other IgGs, do not cross the placenta until 16 weeks and therefore could not play a role in early thyroid embryogenesis. However, we have observed lasting mild thyroid dysfunction in at least two of the seven subjects, and a further infant with a small thyroid lobe which we propose may be due to inhibition of normal TSH-R signalling during the ante- and neonatal period. Karlsson et al. 14 reported a child with permanent damage to the thyroid due to maternal TRAb, which is consistent with our findings. This must be considered when counselling parents of affected infants as there may be some lasting thyroid dysfunction.
TRAb inhibit the binding and action of TSH, and hence are able to prevent uptake of tracer. 6 We demonstrated no uptake of tracer in two of five cases. Brown et al. 4 have previously reported variable uptake of tracer in infants with transient neonatal hypothyroidsm due to maternal TRAb. Our findings and that of Brown et al. 4 demonstrated that babies with the most potent TRAb were less likely to have uptake on scan and had the most profound hypothyroidism.
We have found that 1.6% of cases of CH are transient due to maternal TRAb but suspect that this is an underestimate of the true prevalence. An audit of the follow-up investigations undertaken on the mothers of infants with increased blood spot TSH between January 2003 and December 2004 carried out on behalf of the All Wales Clinical Biochemistry Audit Group demonstrated that the necessary tests to identify transient neonatal hypothyroidism due to TRAb were not always undertaken (Dr Rebekah Pryce, personal communication). In this audit, case-notes of 43 infants with an increased blood spot TSH on newborn screening were retrospectively reviewed. Only 70% (30/43) of mothers of affected infants had had thyroid function tests. Fourteen percent (6/43) of mothers had TRAb and 48% (21/43) had aTPO concentrations measured. Of the 43 mothers, it was noted that two had a history of thyroid dysfunction (one had a previous history of Graves' disease and one was taking thyroxine for treatment for primary hypothyroidism) although neither of these mothers had TRAb measured.
To improve identification of these cases, current practice in Wales is that the screening laboratory specifies that a thyroid function test and a TRAb measurement should be requested on the mother of each infant with a screen positive blood spot TSH in the initial clinical referral. In addition to detecting transient CH due to maternal TRAb, this approach will also detect any factitious increases in TSH due to TSH IgG complexes or other immunoglobulin effects that may interfere with the TSH assay. 15–19
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