Maternal TSH-Receptor Antibodies and TSH Antibodies in Screening for Congenital Hypothyroidism

ABSTRACT. Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyper-thyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

Circulating thyroid antibodies in congenital hypothyroidism.

The role of maternal thyroid antibodies in congenital hypothyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated cAMP production in a rat thyroid cell line, FRTL5. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.     

Circulating Thyroid Antibodies in Congenital Hypothyroidism

ABSTRACT. The role of maternal thyroid antibodies in congenital hypotyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated CAMP production in a rat thyroid cell line, FRTLS. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.     

Thyrotrophin-blocking antibodies in congenital hypothyroidism

The role of transplacental transfer of maternal thyrotrophin (TSH)-blocking antibodies causing congenital hypothyroidism in Southern Chinese children was examined in this study. Twenty-two mothers of 24 patients with congenital hypothyroidism were studied 3-5 years after delivery. None of them had thyroid dysfunction at delivery or at the time of study. None had antithyroglobulin or antimicrosomal antibody. Only one mother was found to have TSH-binding inhibitory immunoglobulin (TBII), and her child had agenesis of the thyroid. This women had Graves disease in remission for 2 years before delivery. None had TSH-stimulated cAMP response inhibitory immunoglobulin (TSII). Ten of the 24 congenital hypothyroid children had transient neonatal hypothyroidism, seven had agenesis of the thyroid, six had dyshormonogenesis and one had a sublingual thyroid. As none of the mothers who had children with transient neonatal hypothyroidism had blocking antibodies at the time of study, the aetiology of the transient neonatal hypothyroidism remains unclear. These data suggest that maternal TSH-blocking antibodies do not play a role in most cases of sporadic congenital hypothyroidism.     

PLACENTAL TRANSFER OF MATERNAL ANTI-RABBIT IgG CAUSING FALSELY ELEVATED TSH LEVELS IN NEONATES

Abstract. Larsson, A., Hedenborg, G. and Carlström, A. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, and the Department of Clinical Chemistry, Karolinska Institute, Danderyd's Hospital, Danderyd, Sweden). Placental transfer of maternal anti-rabbit IgG causing falsely elevated TSH levels in neonates. Acta Paediatr Scand, 70:699,.–Two infants were found to have markedly increased TSH levels, 104 and 154 mU/l of plasma, respectively, in a routine screening programme for congenital hypothyroidism. The recall limit used was 50 mU/l of plasma. On follow-up, both infants were clinically euthyroid and had normal serum T₄ and T₃. The elevated TSH levels were confirmed only with some commercial radioimmunoassay kits–but not with others. Similar results were obtained in TSH assays of samples from their mothers, who had no other biochemical or clinical evidence of thyroid dysfunction. Both mothers had intense contact with rabbits over long periods. The apparent TSH activity was found to be associated with the IgG fraction. It was neutralized by the addition of normal rabbit serum to the samples and was caused by antibodies to rabbit immunoglobulin. The activity was eliminated from the circulation of both infants with a half-life of approximately one month. Apparently, the heterophilic antibodies were of maternal origin and were transferred to the foetus via the placenta. Infants with so-called transient hyperthyrotropinaemia identified in screening programmes have to be reevaluated to exclude false TSH elevations of this type.     

Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibiting immunoglobulin

Transient congenital hypothyroidism due to maternal thyrotrophin binding inhibitor immunoglobulin (TBII), a thyroid-stimulating hormone (TSH)-receptor blocking antibody, is described in three male siblings born to a mother with autoimmune thyroiditis. These cases are believed to be the first described in Australia. The first child was found to have a serum TSH of 565 mU/L and had a negative thyroid scan when presented for neonatal screening. He was treated with thyroxine but became thyrotoxic at 3 months of age when he was on a dosage of 85 μg/m² of body surface area. He was euthyroid 6 months after discontinuation of therapy. Nine years later a second hypothyroid sibling was born, with a serum TSH of 709 mU/L on day 4. Both mother and child were demonstrated to be strongly positive for TBIl. Again this child was able to cease therapy by the age of 9 months. A third sibling, also TBIl positive, was born 12 months after the second. His TSH was 90 mU/L and his serum thyroxine (T₄) was 169 nmol/L. On this occasion, thyroid stimulation-blocking antibody was found to be present in the serum of both mother and child. Thyroxine therapy was ceased at 1 month. The family present a picture of varying degrees of transient neonatal hypothyroidism due to the transplacental passage of a maternal receptor blocking antibody. The condition is self-limiting, resolving when the immunoglobuiin is cleared from the infant's circulation.     

Transient neonatal 'athyreosis' resulting from thyrotropin-binding inhibitory immunoglobulins

Recognition of transient forms of neonatal hypothyroidism is difficult because of the urgency of thyroxine treatment. In the present report the first child born to a mother with Graves' disease developed transient hyperthyroidism during the newborn period. The mother underwent radioactive iodine treatment and was maintained euthyroid on l-thyroxine. Two subsequent children were detected by newborn thyroid screen to have low thyroxine and markedly elevated serum thyrotropin (TSH) levels. Technetium 99 metastable and iodine 123 scans at 22 days of age showed the second child to be athyreotic. The third child was not scanned. All three children were nongoitrous at birth. Patients 2 and 3 had continuous TSH suppression with thyroxine therapy for 3 and 4 years. Thyroid function measurements after discontinuation of therapy for 8 weeks were normal, and both children had normal 123I thyroid scans. The mother was found to have potent TSH-binding inhibitory immunoglobulin (TBII) levels in her serum (85.5%). A fourth child with low thyroxine and elevated TSH was born to a mother on a regimen of l-thyroxine for hypothyroidism. 99mTc scan at 26 days of age showed no thyroid tissue and was normal at 3 months. TBII activity was 35% in the maternal serum and absent in the infant's serum. The above laboratory and clinical data are compatible with the blocking nature of TBII, resulting in transient newborn hypothyroidism and an athyreotic appearance on scan. The TBII measurement can be a useful predictor of neonatal hypothyroidism as well as confirm the transient nature of the disease in newborns.     

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.     

Congenital familial transient hypothyroidism secondary to transplacental thyrotropin-blocking autoantibodies

Three patients demonstrated transient neonatal hypothyroidism, presumably secondary to maternally derived thyrotropin (TSH)-blocking antibodies. Although transient, this disorder might not have been benign in the first child, who exhibited significant developmental delay. A thyroid scan was not helpful in making this diagnosis. Although uncommon, this disorder should be suspected in infants with a maternal history of autoimmune thyroid disease, multiple siblings with congenital hypothyroidism, or a clinical course characterized by continually suppressed TSH levels, despite low doses of levothyroxine sodium replacement. Measurement of TSH-blocking antibodies may be used in the diagnosis of transient neonatal hypothyroidism at birth and is becoming more readily available from reference laboratories. Once diagnosed, the patient may then be prepared for monitored withdrawal of levothyroxine replacement therapy at 2 to 3 years of age and will not be committed to lifelong replacement therapy.     

Thyroid dysfunction in children with Down's syndrome

Thyroid function tests were carried out on 320 children with Down's syndrome aged between 5 d and 10 y. Thyroid function was normal in 230 patients (71.9%) and abnormal in 90 (28.1%). Six patients (1.8%) had primary congenital hypothyroidism, one patient had acquired hypothyroidism and two had transient hyperthyrotropinaemia of the newborn. Sixteen of the remaining 81 patients (25.3%) had compensated hypothyroidism with increased thyroid-stimulating hormone (TSH) levels (11-20 mU l -1 ). Their T 4 levels were found to be either normal or close to the lower limit of normal. These cases were started on thyroxine therapy. Sixty-five of the 81 patients had a mild compensated hypothyroidism with mild TSH elevation (6-10 mU l -1 ). None of the patients had hyperthyroidism. The antithyroid antibodies were positive in the acquired hypothyroidism case.

Conclusion: The prevalence of congenital hypothyroidism was 1.8% in children with Down's syndrome while 25.3% of them had compensated hypothyroidism. It is suggested that Down's syndrome patients with normal thyroid functions and those with compensated hypothyroidism should be followed annually and every 3 mo, respectively. Besides congenital hypothyroidism cases, those with TSH levels between 11 and 20 mU l -1 may benefit from treatment with low-dose thyroxine.     

Thyroid function in young children with Down syndrome

A retrospective review of thyroid function tests (TFTs) was performed on 49 young children (aged 4 months to 3 years) with Down syndrome compared with age-matched controls screened for hypothyroidism because of developmental delay or failure to thrive. Three of the 49 children with Down syndrome had congenital hypothyroidism; of the three, one had Hirschsprung's disease and two had duodenal atresia. Thyroiditis was uncommon, with only two children having thyroid antibodies present: one had acquired hypothyroidism and the other acquired hyperthyroidism. Twenty-seven percent of the Down syndrome cohort had mildly increased thyrotropin (TSH) and normal thyroxine levels. When compared with children with Down syndrome who had normal TFTs, no significant differences in sex, growth rate, maternal age, associated anomalies, developmental or specific thyroid symptoms were present. Transient elevations of TSH level were common in children with Down syndrome whether or not TSH values were initially normal or elevated. Routine neonatal and sequential thyroid screening in young children with Down syndrome is warranted.     

Borderline congenital hypothyroidism in the neonatal period

One of the most important etiological factors causing prolonged jaundice in the neonatal period is congenital hypothyroidism. Some infants may have abnormal thyroid function test results rather than overt congenital hypothyroidism. Although serum TSH levels are accepted as diagnostic when >20 microIU/l, TSH values higher than 7 microIU/ml cause a hypometabolic condition. In this study, we evaluated infants who had prolonged jaundice for hypothyroidism. A hundred and ten infants suffering from prolonged jaundice were admitted to our clinic during the study period. Among them, 61 infants had normal thyroid function results. Six patients had overt primary hypothyroidism. TRH stimulation test was administered to the 43 patients with mildly elevated TSH levels of between 5 and 20 microIU/ml. Peak TSH values were above 35 microIU/ml in seven patients, and these were considered as having an exaggerated response (borderline hypothyroidism). During the neonatal period, prolonged jaundice is a valuable diagnostic clue for hypothyroidism. In addition, the TRH stimulation test can be a diagnostic tool in evaluating infants with mildly abnormal thyroid function test results.     

The differing outcomes of hyperthyrotropinaemia

Hyperthyrotropinaemia, in which normal levels of T4 occur in association with raised TSH, is picked up on neonatal screening. The outcome of children with persistent hyperthyrotropinaemia is uncertain. The study objective was to evaluate the outcome of children with the persistent form of hyperthyrotropinaemia. We carried out a retrospective analysis on children who attended one institution over the last 20 years with this diagnosis. Eight children were diagnosed with hyperthyrotropinaemia lasting more than 3 months in total. Four had a transient form lasting between 3 and 18 months in total. Three continue to have persistently raised TSH at 5, 9 and 17 years, respectively. One patient became biochemically hypothyroid at 1 year of age requiring treatment with replacement thyroxine. All of our group had normal growth and development. We recommend that thyroid function monitoring should continue in all children with hyperthyrotropinaemia until the thyroid function tests have normalised.     

Neonatal seizures

AIMS—To define the aetiology of neonatal transient hypothyroidism (NTH) and recommend preventive measures.METHODS—Maternal and perinatal clinical data on the use of antiseptics, drugs, and contrast agents containing iodine were collected from 40 subjects. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroxine (T4), thyroglobulin (TG), TSH receptor antibodies, thyroid peroxidase antibodies and urinary iodine were measured in random neonatal samples. In the mothers with known or suspected thyroid disorders, TSH, FT4, TSH receptor antibodies and thyroid peroxidase antibodies were also measured.RESULTS—The NTH aetiology was identified in 85% of cases. More than 50% of the babies with transient hypothyroidism had been exposed to iodine; maternal transfer of antibodies had occurred in a third of them.CONCLUSIONS—It is suggested that the practice of using iodine containing disinfectants should be withdrawn, and chlorhexidine substituted instead; that pregnant women should be advised of the adverse effects of using iodine products; and that thyroid function should be monitored whenever iodine is used.     

Usefulness of serum thyrotropin-binding inhibitory index measurements in infantile hypothyroidism. Relationship to serum thyrotropin concentrations

Transplacental passage of thyrotropin (TSH)-binding inhibitory immunoglobulins may result in transient congenital hypothyroidism. We measured serum TSH-binding inhibitory index (TBII) in 11 infants with abnormal screening findings using a commercially available kit. Two of the infants, who were siblings, had markedly elevated TBII values (90% and 100%, respectively), as did their mother (89%, 100%), and had a clinical course consistent with transient antibody-mediated hypothyroidism. Four other infants had a borderline or mildly elevated TBII that was not present in maternal serum, suggesting that endogenous TSH was being measured in this assay. The TBII was measured in the sera of 18 additional children with primary hypothyroidism and in human TSH standards from 25 to 2000 mU/L. Increasing concentrations of TSH were associated with a linear increase in TBII. Measurement of TBII by this method may identify infants with transient antibody-mediated hypothyroidism, although simultaneous assessment of maternal serum is necessary.     

Genetic Analysis in Children with Transient Thyroid Dysfunction or Subclinical Hypothyroidism Detected on Neonatal Screening

About 30% of children with elevated TSH levels during neonatal screening have a transient form of disorder. On the other hand, it has been reported that subclinical hypothyroidism persists in late childhood in about 30% of children found to be false-positive during neonatal screening. The aim of this study was to determine whether transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening are influenced by genetic background. The TSH receptor (TSHR), thyroid peroxidase (TPO) and dual oxidase 2 (DUOX2) genes, for which it has been reported that heterozygous defects cause neonatal transient thyroid dysfunction, were analyzed. Nine children with transient thyroid dysfunction or subclinical hypothyroidism detected during neonatal screening were studied. One child was heterozygous for a TSHR gene mutation (R450H), and another child was heterozygous for a TPO gene mutation (P883S). No children with mutation of the DUOX2 gene were identified. Genetic background may contribute to development of transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening.     

Transient infantile hyperthyrotropinaemia. Report of a case.

A case of transient hyperthyrotropinaemia was found by mass screening for neonatal hypothyroidism using the paired TSH assay method. The patient was a baby boy born at term after a normal pregnancy who grew without any abnormal signs or symptoms. For the first 7 months after birth, his serum TSH was abnormally high while his total serum T4, T3, and free T4, T3 were within normal limits, exept for slightly low free T4 level at 7 months. The raised serum TSH decreased spontaneously to within normal limits after he was 9 months old.     

Thyrotropin binding inhibitor immunoglobulin. Its pathogenetic importance in hypothyroidism

Two patients with hypothyroidism had detectable serum levels of thyrotropin binding inhibitor immunoglobulin (TBII). Patient 1 was a newborn infant who had transient neonatal hypothyroidism due to transfer of TBII from the mother with nongoitrous autoimmune thyroiditis. Patient 2 was an 8-year-old girl with Down's syndrome who presented with signs of myxedema and central precocious puberty. She had no goiter, and the recognition of thyroid disease was delayed; the histological diagnosis of chronic lymphocytic thyroiditis was established by aspiration biopsy, and TBII had strong thyroid adenyl cyclase-inhibiting activity in vitro. It appears that TBII may be pathogenetically important for occurrence of neonatal hypothyroidism and nongoitrous autoimmune thyroiditis without goiter.     

Dopamine suppresses thyroid-stimulating hormone secretion in neonatal hypothyroidism

The infusion of dopamine, a hypophysiotropic catecholamine, which inhibits release of thyroid stimulating hormone (TSH), is the inotropic therapy of first choice in neonatal intensive care. Newborns with primary hypothyroidism are at increased risk of cardiocirculatory morbidity and are screened by measuring serum TSH concentrations. In an infant with both congenital heart disease and neonatal hypothyroidism, withdrawal of dopamine infusion was documented to evoke a doubling of serum TSH levels within 40 min, a finding suggestive of an inhibitory effect of dopamine administration on neonatal TSH hypersecretion. As a result, dopamine therapy may be a pitfall in TSH screening for neonatal hypothyroidism.