Thyroid scintigraphy differentiates subtypes of congenital hypothyroidism.

INTRODUCTION: UK screening for congenital hypothyroidism (CH) is based on dried blood spot Thyroid Stimulating Hormone (TSH). Scintigraphy may identify CH subtypes classified as dysplasia, gland in situ (GIS) and ectopia, but is not performed in all centres. We retrospectively investigated the role of scintigraphy to identify CH subtypes in a single tertiary centre cohort. METHODS: Babies who screened positive for CH between 2007 and 2017 were studied (n=418 of 534 783). Scintigraphy outcomes were correlated with TSH and levothyroxine dose. GIS patients were analysed for 3-year outcomes. RESULTS: 303 patients started levothyroxine. Scintigraphy demonstrated three subtypes: GIS (n=139, 46%) ectopia (n=84, 28%) and dysplasia (n=80, 26%). Three-year follow up demonstrated permanence in 54% of 37 GIS cases. DISCUSSION: Thyroid scintigraphy differentiates subtypes of CH and suggests a higher than expected proportion of patients with GIS and ectopia. CH is permanent in half of those with GIS.

Haploinsufficiency of NKX2-1 in Brain-Lung-Thyroid Syndrome with Additional Multiple Pituitary Dysfunction.

INTRODUCTION: Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome incorporating primary hypothyroidism, respiratory distress, and neurological disturbances. CASE PRESENTATION: We report a patient presenting in the neonatal period with multiple pituitary hormone deficiency including central hypothyroidism and hypoadrenalism, growth hormone deficiency, undetectable gonadotrophins, and a small anterior pituitary on MRI. CGH microarray revealed haploinsufficiency for NKX2.1 and during subsequent follow-up, she has exhibited the classic triad of brain-lung-thyroid syndrome with undetectable tissue on thyroid ultrasonography. Whilst the role of NKX2-1 is well described in murine pituitary development, this report constitutes the first description of multiple pituitary dysfunction in humans associated with the syndrome and haploinsufficiency NKX2-1. CONCLUSION: The report highlights a potential need for pituitary screening in patients with established brain-lung-thyroid syndrome and implicates NKX2.1 in human pituitary disease.

Thyroid scintigraphy in three-year-old children with congenital hypothyroidism in correlation with neonatal TSH.

INTRODUCTION: A large number of congenital hypothyroidism (CH) cases in Iran are transient. This study was designed to investigate the aetiology of permanent CH (PCH) by thyroid scintigraphy (TS) and its relationship with the first diagnostic thyrotropin (TSH). MATERIAL AND METHODS: During 12 years (2005-2017) of CH screening in southwest Iran, all infants referred with the diagnosis of CH were followed until their third birthday, when they were re-evaluated for serum T4, TSH after discontinuing the treatment for 3-4 weeks. If the last test indicated a PCH state (TSH >10 mU/L with any levels of T4), TS was performed, and, based on the results, the patients were categorised as agenesis, dysgenesis (sublingual, thyroglossal cyst), and normal/diffuse goitre (indicating dyshormonogenesis). RESULTS: After excluding all transient CH subjects, 224 permanent CH cases were enrolled (52.7% female). Seasonal distributions were as follows: spring: 25.7%, summer: 27.9%, autumn: 20.3%, and winter: 26.1%. No significant differences were found between females and males and the different modes of delivery (55.4% were delivered by caesarean section) regarding T4, TSH (p > 0.05). Of a total of 213 performed scans, 20.7% had agenesis, 36.2% had dysgenesis, and 43.2% were normal or goitrous. Those with agenesis/dysgenetic thyroid had a lower T4 and a higher TSH than those with normal scans. However, the differences were not significant. Compared to those who had TSH < 40 mU/L, patients with TSH ≥ 40mU/L had 46% (95% CI: 1.06-2.02) more risk of agenesis or dysgenesis in TS. CONCLUSIONS: More than 40% of PCH are caused by dyshormonogenesis in Iran. Having a TSH ≥ 40 mU/L after the first week of life significantly raises the probability of thyroid agenesis/dysgenesis as the cause.

Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis

ABSTRACT Objective: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. Subjects and methods: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. Results: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). Conclusions: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.

Normative Data of Thyroid Gland Volume in South Indian Neonates and Infants.

OBJECTIVE: To establish normative ultrasound data for thyroid gland volume in South Indian neonates and infants and compare with abnormal sonological features of thyroid in congenital hypothyroidism (CH) to explore thyroid ultrasound utility as a supportive screening tool to newborn screening programs for early detection of CH. METHODS: In view of impact of geo ethnic factors, varying growth velocities and body mass indices of human population worldwide, specific regional, age and gender related reference data for thyroid gland size and volume are vital. This study was an offshoot of ICMR pilot New Born Screening (NBS) project for CH. Formula used for thyroid volume estimation was ellipsoidal formula D1 x D2 x D3 × 0.523. It was a prospective observational study. The neonates who screened negative for Thyroid Stimulating Hormone (TSH) with repeat normal serum TSH and free thyroxine were selected. One hundred fifty seven infants were enrolled which included 99 boys and 58 girls. The study population included children in age groups from 3 d to 1 y six months. RESULTS: Data analysis was done by descriptive method and unpaired t test. Mean thyroid volume was 0.26 ml with 0.27 ml in boys and 0.24 ml in girls. Statistically significant "p value" was noted in single lobe measurements among boys and girls. CONCLUSIONS: Thyroid gland volume normative data play a key role in evaluation of thyroid sonological abnormalities in CH and there is effective utility of ultrasound as a supportive diagnostic and prognostic screening tool for early detection of CH.

Congenital hypothyroidism due to ectopic sublingual thyroid gland in Prader-Willi Syndrome: a case report.

BACKGROUND: Thyroid gland disorders are variably associated with Prader-Willi syndrome (PWS). Many of the clinical features in newborns with PWS are similar to those found in congenital hypothyroidism (CH). CASE PRESENTATION: We report a case of a girl with CH and PWS. At the age of 9 months CH caused by an ectopic sublingual thyroid was diagnosed, and hormone replacement therapy was started. In spite of this treatment a decrease in growth velocity, weight excess and delayed development were observed. At the age of 9 years PWS was suspected on the basis of phenotype and genetic tests confirmed a maternal uniparental disomy of chromosome 15. This is the second reported case of hypothyroidism due to an ectopic sublingual thyroid gland in PWS suggesting that, although rare, an association between CH and PWS may exist. In our case diagnosis of PWS was delayed because mental retardation, hypotonia, obesity and short stature were initially attributed to hypothyroidism. CONCLUSIONS: In this context PWS should be considered in obese children with CH who do not improve adequately with l-thyroxine therapy. Also, thyroid function in all PWS children should be assessed regularly in order to avoid delayed diagnosis of hypothyroidism.

Timing of thyroid ultrasonography in the etiological investigation of congenital hypothyroidism

ABSTRACT Objectives To describe the findings of thyroid ultrasonography (T-US), its contribution to diagnose congenital hypothyroidism (CH) and the best time to perform it. Subjects and methods Forty-four patients with CH were invited to undergo T-US and 41 accepted. Age ranged from 2 months to 45 years; 23 patients were females. All were treated with L-thyroxine; 16 had previously undergone scintigraphy and 30 had previous T-US, which were compared to current ones. Results At the current T-US, the thyroid gland was not visualized in its normal topography in 10 patients (24.5%); 31 T-US showed topic thyroid, 17 with normal or increased volume due to probable dyshormonogenesis, 13 cases of hypoplasia and one case of left-lobe hemiagenesis. One patient had decreased volume due to central hypothyroidism. Scintigraphy scans performed 3-4 years earlier showed 100% agreement with current results. Comparisons with previous T-US showed concordant results regarding thyroid location, but a decrease in current volume was observed in eight due to the use of L-thyroxine, calling the diagnosis of hypoplasia into question. Conclusions The role of T-US goes beyond complementing scintigraphy results. It allows inferring the etiology of CH, but it must be performed in the first months of life. An accurate diagnosis of CH will be attained with molecular study and the T-US can guide this early assessment, without therapy withdrawal.

Ultrasonography of various thyroid diseases in children and adolescents: a pictorial essay.

Thyroid imaging is indicated to evaluate congenital hypothyroidism during newborn screening or in cases of a palpable thyroid mass in children and adolescents. This pictorial essay reviews the ultrasonography (US) of thyroid diseases in children and adolescents, including normal thyroid gland development, imaging features of congenital thyroid disorders (dysgenesis, [aplasia, ectopy, hypoplasia], dyshormonogenesis, transient hypothyroidism, thyroglossal duct cyst), diffuse thyroid disease (Grave's disease, Hashimoto's thyroiditis, and suppurative thyroiditis), and thyroid nodules. The primary imaging modalities for evaluating thyroid diseases are US and radionuclide scintigraphy. Additionally, US can be used to guide aspiration of detected nodules.

A case of congenital hypothyroidism in PHACE syndrome.

Although hemangiomas, benign tumors of vascular origin, are very common among children and represent the most frequent benign tumor at that age, their association with other malformations constitutes a rare neurocutaneous disorder called PHACE syndrome. This condition is characterized by posterior fossa anomalies, hemangioma of the face, arterial alterations, cardiac defects, and eye anomalies (as represented by the acronym PHACE); sternum defects, endocrinopathies, and thyreopathies may be present as well. In this report, we describe a case of congenital hypothyroidism due to an empty thyroid site, as demonstrated by ultrasound, in an Italian child.

Is the incidence of congenital hypothyroidism really increasing? A 20-year retrospective population-based study in Québec.

CONTEXT: Congenital hypothyroidism (CH) is reportedly increasing in the United States, possibly reflecting changes in screening methods. In Québec, the same initial TSH cutoff (15 mU/liter) has been used for the last 20 yr, but in 2001, the cutoff was decreased from 15 to 5 mU/liter for the second test, which is requested when TSH is intermediate (15-30 mU/liter) on the first. OBJECTIVES: Our objective was to assess the incidence of CH over the last 20 yr in Québec. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: This is a population-based retrospective study. Incidences by etiology based on thyroid scintigraphy with technetium were compared between 1990-2000 and 2001-2009. RESULTS: Of 1,660,857 newborns over 20 yr, 620 had CH (incidence 1:2679). Etiology was dysgenesis (n = 389, 1:4270), either ectopy (n = 290) or athyreosis (n = 99), goiter (n = 52, 1:31,940), normal-size gland in situ (n = 115, 1:14,442), and unknown (n = 64, 1:25,950). The new screening algorithm identified 49 additional cases (i.e. 25 normal-size gland in situ, 12 unknown etiology, 10 ectopies, and two goiters). Consequently, the incidence of normal-size gland in situ or of unknown etiology more than doubled (1:22,222 to 1:9,836, P = 0.0015; and 1:43,824 to 1:17,143, P = 0.0018, respectively) but that of dysgenesis and goiter remained stable. Had the 1990-2000 algorithm been applied in 2001-2009, no change in incidence would have been observed in any category. CONCLUSION: Estimating the incidence of CH is influenced by minimal changes in TSH screening cutoffs. Lower cutoffs identify additional cases that have predominantly functional disorders whose impact on intellectual disability, if left untreated, remains to be determined.

Thyroid imaging in children.

Ultrasonography (US) and radionuclide thyroid scanning are the imaging modalities of choice in the evaluation of the thyroid gland in children. The main normal US patterns of the thyroid gland are reviewed. In early infancy, thyroid imaging is usually performed in the context of congenital hypothyroidism (CH). The aetiological diagnosis of CH is usually based on the combined use of US and radionuclide thyroid scanning. A detailed description of thyroid abnormalities observed in CH is given. Thyroid dysgenesis includes athyreosis, 'empty' thyroid area with ectopic thyroid tissue and thyroid hypoplasia (global hypoplasia and thyroid hemiagenesis). Mild thyroid developmental anomalies (pyramidal lobe, thyroglossal duct cysts, thyroid hemiagenesis) may be observed in euthyroid patients or among first-degree relatives of a CH population with thyroid dysgenesis. A normally located gland (goitre, normal-sized thyroid gland or hypoplastic thyroid gland) may also be observed in patients with CH. The main patterns observed in chronic and acute thyroiditis, in hyperthyroidism and thyroid tumours are described. Moreover, fetuses and neonates born to mothers with Graves' disease are at risk of thyroid dysfunction and goitre due to hypothyroidism in relation to excessive maternal treatment or to maternal hyperthyroidism which may be observed with fetal US.

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.

Benign thyroid disease: what is the role of nuclear medicine?

Nuclear medicine is directly involved in both the diagnosis and treatment of benign thyroid disease, which requires an understanding of the pathophysiology and management of thyroid disorders in addition to expertise in nuclear methodology. Thyroid uptake and imaging, the principal nuclear tests in thyroid disease, may be used as follows: (1) Differential diagnosis of hyperthyroidism: A very low thyroid uptake suggests destructive ("subacute") thyroiditis, a self-limited disorder, whereas a normal or elevated uptake is consistent with toxic nodular goiter and Graves' disease. Scintigraphic characteristics also help differentiate between nodular and Graves' disease. (2) Function of thyroid nodules: Fine-needle aspiration biopsy with cytological examination (FNAB) is used routinely to assess for malignancy in thyroid nodules. Scintigraphy may be of assistance before FNAB. "Hot" nodules are generally benign and do not require FNAB, while "cold" nodules may be malignant. (3) Differential diagnosis of congenital hypothyroidism: Scintigraphy combined with ultrasound examination may be used to identify such conditions as thyroid agenesis, dyshormonogenesis, and incomplete thyroid descent. Treatment of Graves' disease and toxic nodular disease with (131)I may require greater clinical involvement and decision analysis compared with thyroid uptake and imaging. The following aspects of treatment are particularly important: (1) Risk: Radioiodine treatment may occasionally aggravate hyperthyroidism, Graves' ophthalmopathy, and airway obstruction caused by large, nodular goiters. Alternative treatments, including the temporary use of antithyroid drugs, and surgery for nodular goiters, may be considered. (2) Radioiodine dose: Cure of hyperthyroidism with a single (131)I treatment is desirable, though not always possible. Such factors as a large goiter, severe hyperthyroidism, and prior propylthiouracil therapy, may contribute to treatment failure. (3) Informed consent: A detailed discussion with the patient regarding the clinical risks, outcomes, and side effects of (131)I is a critical component of successful management.

Role of scintigraphy in congenital thyroid anomalies.

Thyroid scintigraphy using Tc-99m pertechnetate is a frequently performed procedure in routine nuclear medicine practice. The indications for thyroid scintigraphy are investigation of hyperthyroidism, nodularity of the gland, cause of thyroid stimulating hormone elevation and localization of an ectopic thyroid gland. In the pediatric population, the most common request is for the evaluation of neonatal hypothyroidism. This imaging procedure is helpful in the identification of the underlying cause as well as in making a differential diagnosis. Early diagnosis is essential for appropriate therapy planning in this age group, and thyroid scintigraphy provides important diagnostic data. This article is written to review the scintigraphic findings in various congenital thyroid anomalies and to underline its use in the differential diagnosis.

The continuing importance of thyroid scintigraphy in the era of high-resolution ultrasound.

At the molecular level, the uptake of radioiodine and pertechnetate is proportional to the expression of the thyroidal sodium/iodine symporter (NIS). Qualitative and quantitative scintigraphic evaluation of the thyroid is performed with a gamma camera fitted with an on-line computer system and enables determination of the iodine uptake or the technetium uptake (TCTU) as an iodine clearance equivalent. Despite new molecular genetic insights into congenital hypothyroidism, the iodine-123 or pertechnetate scan remains the most accurate test for the detection of ectopic thyroid tissue. Following the identification of specific mutations of the genes coding for the NIS, thyroid peroxidase and pendrin, the discharge test has lost its role in establishing the diagnosis of inherited dyshormonogenesis, but it is still of value in the assessment of defect severity. In PDS mutations the test can be used to establish the diagnosis of syndromic disease. Quantitative pertechnetate scintigraphy is the most sensitive and specific technique for the diagnosis and quantification of thyroid autonomy. The method has proved to be valuable in risk stratification of spontaneous or iodine-induced hyperthyroidism, in the estimation of the target volume prior to radioiodine therapy and in the evaluation of therapeutic success after definitive treatment. In iodine deficiency areas the thyroid scan remains indispensable for the functional characterisation of a thyroid nodule and is still a first-line diagnostic procedure in cases of suspected thyroid malignancy. This is especially of importance in patients with Graves' disease, among whom a relatively high prevalence of cancer has been found in cold thyroid nodules. While determination of the TCTU is without any value in the differentiation between autoimmune thyroiditis and Graves' disease in most cases, it is of substantial importance in the differentiation between hyperthyroid autoimmune thyroiditis and Graves' disease.

Effects of protracted hypothyroidism on pituitary function and structure in endemic cretinism.

Pituitary function and structure were assessed in 69 endemic cretins from western China. In hypothyroid cretins (TSH greater than 10 mIU/l), CT imaging of the pituitary revealed adenoma in five of 20 (25%) and partially empty sella (PES) in a further eight of 20 (40%). The majority of tumours were microadenomas and showed a relation with higher levels of serum TSH but not with duration of hypothyroidism. Dynamic pituitary testing with TRH and GnRH in four patients with adenoma on CT gave a flat TSH response but significant rises in serum PRL, GH, LH and FSH concentrations. Hyperprolactinaemia (greater than 350 mIU/l) was present in hypothyroid cretins only (13 of 26; 50%) and serum PRL showed a curvilinear relation with serum TSH levels (r = 0.7, P less than 0.0001). Hypogonadism was seen in approximately half the cretins with high PRL levels. Our data suggest that severe protracted thyroid hormone deficiency may result in thyrotrophin adenomas of the pituitary gland. Disturbances of growth, puberty, and sexual function in endemic cretins are explained by the secondary effects of thyroid hormone deficiency on pituitary function.

Breast carcinoma, thyroid carcinoma, and T3 thyrotoxicosis in a male cretin.

A male patient with clinical and radiographic evidence of cretinism was found to have T3 thyrotoxicosis. The cause was thought to be a well-differentiated follicular carcinoma of the thyroid. Although the disease was not documented, the patient probably had long-standing hypothyroidism. Untreated primary thyroid failure accompanied by high serum thyroid stimulating hormone (TSH) may be carcinogenic to the thyroid. The association of thyroid abnormalities and male breast carcinoma is discussed.