A European Network for the Investigation of Gender Incongruence in adolescents.

BACKGROUND: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender Incongruence (ENIGI). However, data on the effects of puberty suppression (PS) and GAHT in transgender and gender diverse (TGD) youth are limited, although these data are of crucial importance, given the controversies surrounding this treatment. AIM: We sought to present a detailed overview of the design of the ENIGI Adolescents study protocol, including the first baseline data. METHODS: The ENIGI Adolescents study is an ongoing multicenter prospective cohort study. This study protocol was developed by 3 European centers that provide endocrine care for TGD adolescents and were already part of the ENIGI collaboration: Amsterdam, Ghent, and Florence. OUTCOMES: Study outcomes include physical effects and side effects, laboratory parameters, bone mineral density, anthropometric characteristics, attitudes toward fertility and fertility preservation, and psychological well-being, which are measured in the study participants during PS and GAHT, up to 3 years after the start of GAHT. RESULTS: Between November 2021 and May 2023, 172 TGD adolescents were included in the ENIGI Adolescents protocol, of whom 51 were assigned male at birth (AMAB) and 121 were assigned female at birth (AFAB); 3 AFAB participants reported a nonbinary gender identification. A total of 76 participants were included at the start of PS, at a median (IQR) age of 13.7 (12.9-16.5) years in AMAB and 13.5 (12.4-16.1) years in AFAB individuals. The remaining 96 participants were included at start of GAHT, at a median (IQR) age of 15.9 (15.1-17.4) years in AFAB and 16.0 (15.1-16.8) years in AMAB individuals. At the time of this report the study was open for inclusion and follow-up measurements were ongoing. CLINICAL IMPLICATIONS: In response to the rising demand for gender-affirming treatment among TGD youth, this ongoing study is fulfilling the need for prospective data on the effects and safety of PS and GAHT, thus providing a foundation for evidence-based healthcare decisions. STRENGTHS AND LIMITATIONS: This study has a strong multicenter, prospective design that allows for systematic data collection. The use of clinical and self-reported data offers a broad range of outcomes to evaluate. Nevertheless, the burden of additional measurements and questionnaires may lead to withdrawal or lower response rates. Few participants with a non-binary gender identity have been included. CONCLUSION: With the ENIGI Adolescents study we aim to create a comprehensive dataset that we can use for a wide range of studies to address current controversies and uncertainties and to improve healthcare for TGD adolescents.

Long-term oncological outcomes of follicular thyroid cancer in adolescents and young adults: A nationwide population-based study.

BACKGROUND: Follicular thyroid carcinoma (FTC) in adolescents and young adults (AYAs) is rare and data on long-term oncological outcomes are scarce. This study aimed to describe the long-term recurrence and survival rates of AYAs with FTC, and identify risk factors for recurrence. METHODS: This is a retrospective cohort study combining two national databases, including all patients aged 15-39 years, diagnosed with FTC in The Netherlands between 2000 and 2016. Age, sex, tumor size, focality, positive margins, angioinvasion, pT-stage, and pN-stage were included in a Cox proportional hazard model to identify risk factors for recurrence. RESULTS: We included 192 patients. Median age was 31.0 years (IQR 24.7-36.3) and the male to female ratio was 1:4.1. Most patients presented with a minimally invasive FTC (MI-FTC) (95%). Five patients presented with synchronous metastases (2.6%), including two with locoregional metastases (1%) and three with distant metastases (1.6%). During a median follow-up of 12.0 years, three patients developed a recurrence (1.6%), of which one patient developed a local recurrence (33%), and two patients a distant recurrence (67%). Five patients died during follow-up (2.6%). Cause of death was not captured. A Cox proportional hazard model could not be performed due to the low number of recurrences. CONCLUSIONS: FTC in AYAs is generally characterized as a low-risk tumor, as it exhibits a very low recurrence rate, a high overall survival, and it typically presents as MI-FTC without synchronous metastases. These findings underscore the favorable long-term oncological prognosis of FTC in AYAs.

Low free thyroxine and normal thyroid-stimulating hormone in infants and children: possible causes and diagnostic work-up.

Screening for hypo- or hyperthyroidism in adults is generally done by measuring the serum thyrotropin (thyroid-stimulating hormone, TSH) concentration. This is an efficient approach in case of suspected acquired thyroid disease. However, in infants and children, congenital hypothalamus-pituitary-thyroid (HPT) axis disorders also need to be considered, including primary and central congenital hypothyroidism, and even rarer thyroid hormone receptor and transporter defects. In primary congenital hypothyroidism, TSH will be elevated, but in the other congenital HPT axis disorders, TSH is usually within the normal range. Free thyroxine (FT4) assessment is essential for the diagnosis in these conditions.Conclusion: Here we discuss a number of rare congenital HPT axis disorders in which TSH is normal, but FT4 is low, and provide a clinical algorithm to distinguish between these disorders. What is Known: • A single thyroid-stimulating hormone (TSH) measurement is an appropriate screening method for primary hypothyroidism. • For central hypothyroidism and rare thyroid hormone receptor and transporter defects a free thyroxine (FT4) measurement is essential for the diagnosis because TSH is usually normal. What is New: • Here we present a new problem-oriented clinical algorithm including a diagnostic flow-chart for low FT4 and normal TSH in infants and children.

Mutations in IRS4 are associated with central hypothyroidism.

BACKGROUND: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. METHODS: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. RESULTS: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. CONCLUSIONS: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.

The development of hypothalamic obesity in craniopharyngioma patients: A risk factor analysis in a well-defined cohort.

BACKGROUND: Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. PROCEDURE: A retrospective cohort consisting of all CP patients treated between 2002 and 2012 in two university hospitals was identified. Multivariable logistic regression was used to study the associations between preoperative BMI, age at diagnosis, tumor volume, performed surgical resection, and presence of HO at follow-up. RESULTS: Thirty-five patients (21 children and 14 adults) were included. Median follow-up time was 35.6 months (4.1-114.7). Four patients were obese at diagnosis. HO was present in 19 (54.3%) patients at last follow-up of whom eight were morbidly obese. Thirteen (37.1%) patients underwent partial resection (PR) and 22 (62.9%) gross total resection (GTR). GTR was related to HO (OR 9.19, 95% CI 1.43-59.01), but for morbid HO, obesity at diagnosis was the only risk factor (OR 12.92, 95% CI 1.05-158.73). EFS in patients after GTR was 86%, compared to 42% after PR (log-rank 9.2, P = 0.003). Adjuvant radiotherapy after PR improved EFS (log-rank 8.2, P = 0.004). Panhypopituitarism, present in 15 patients, was mainly seen after GTR. CONCLUSIONS: HO is less frequent after PR than after GTR, but PR cannot always prevent the development of morbid obesity in patients with obesity at diagnosis. PR reduces the occurrence of panhypopituitarism. When developing a treatment algorithm, all these factors should be considered.

A specific mutation in TBL1XR1 causes Pierpont syndrome.

BACKGROUND: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. METHODS: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. RESULTS: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin ß-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. CONCLUSIONS: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation.

Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome.

BACKGROUND: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. METHODS: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. RESULTS: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. CONCLUSION: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.

Changes in body mass index in long-term childhood cancer survivors.

BACKGROUND: Previous studies have reported changes in the body mass index (BMI) with time in childhood cancer survivors (CCSs) during follow-up. The limitations of these studies include that they described only a subgroup of survivors or used questionnaires with self-reported heights and weights. The goal of this study was to examine BMI in a large cohort of long-term CCSs and relate this to the BMI at diagnosis, age, sex, tumor type, treatment, and endocrine defects. METHODS: All patients treated for childhood cancer at the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 who had survived for at least 5 years were eligible for inclusion. For 893 CCSs with a mean follow-up of 14.9 years, the BMI at the late effects outpatient clinic was compared with the BMI for the general Dutch population. RESULTS: For girls, an increased prevalence of obesity was found. Risk factors for developing a high BMI at follow-up were a younger age and a high BMI at diagnosis and treatment with cranial radiotherapy. A significantly increased prevalence of severe underweight was found in all adult subgroups except for females aged 26 to 45 years. An association was found between a low BMI at diagnosis and a low BMI at follow-up. No treatment-related variables could be related to changes in BMI. CONCLUSIONS: The BMI at diagnosis is one of the most important predictors for the BMI at follow-up, and this suggests an important genetic or environmental cause. Adult CCSs are at high risk for developing severe underweight at follow-up. Future studies should focus on the causes and clinical consequences of underweight.

High prevalence of early hypothalamic-pituitary damage in childhood brain tumor survivors: need for standardized follow-up programs.

INTRODUCTION: Childhood brain tumor survivors (CBTS) are at increased risk to develop endocrine disorders. Alerted by two cases who experienced delay in diagnosis of endocrine deficiencies within the first 5 years after brain tumor diagnosis, our aim was to investigate the current screening strategy and the prevalence of endocrine disorders in survivors of a childhood brain tumor outside of the hypothalamic-pituitary region, within the first 5 years after diagnosis. PROCEDURES: Firstly, we performed a retrospective study of 47 CBTS treated in our center, diagnosed between 2008 and 2012. Secondly, the literature was reviewed for the prevalence of endocrine disorders in CBTS within the first 5 years after diagnosis. RESULTS: Of 47 CBTS eligible for evaluation, in 34% no endocrine parameters had been documented at all during follow up. In the other 66%, endocrine parameters had been inconsistently checked, with different parameters at different time intervals. In 19% of patients an endocrine disorder was found. At literature review 22 studies were identified. The most common reported endocrine disorder within the first 5 years after diagnosis was growth hormone deficiency (13-100%), followed by primary gonadal dysfunction (0-91%) central hypothyroidism (0-67%) and primary/subclinical hypothyroidism (range 0-64%). CONCLUSION: Endocrine disorders are frequently seen within the first 5 years after diagnosis of a childhood brain tumor outside of the hypothalamic-pituitary region. Inconsistent endocrine follow up leads to unnecessary delay in diagnosis and treatment. Endocrine care for this specific population should be improved and standardized. Therefore, high-quality studies and evidence based guidelines are warranted.

Approach to the Patient: Challenging Cases of Pediatric Thyrotoxicosis.

Graves' disease (GD) is the leading cause of hyperthyroidism in children. However, compared to adults GD in children is a rare condition. In a recent guideline issued by the European Thyroid Association the diagnostic evaluation and treatment of pediatric GD is described extensively. In this article we go beyond the guideline and describe the potential challenges of establishing the right etiology of thyrotoxicosis in children, illustrated by cases of thyroid hormone resistance, autonomous functioning thyroid nodules and subacute thyroiditis with a thyrotoxic phase. In addition, we report therapeutic challenges in pediatric GD such as recurrent immunological flare-ups under anti-thyroid drug (ATD) treatment, innovative ways to improve ATD compliance and the role of definitive treatment in persistent complaints of malaise under ATD treatment.

Fetal Thyrotoxicosis due to Maternal TSH Receptor Stimulating Antibodies Causes Infant Central Hypothyroidism.

INTRODUCTION: Women with a current diagnosis or past history of Graves' disease (GD) are at risk of developing fetal thyrotoxicosis (FT) during pregnancy when they are inadequately treated, or because of placental passage of TSH receptor antibodies (TRAb). It is known that FT induced by high maternal thyroid hormone concentrations may result in infant (central) hypothyroidism. CASE PRESENTATION: In a euthyroid woman with a history of GD treated with radioactive iodide (I131), persistently high levels of maternal TRAb resulted in recurrent FT during two separate pregnancies, followed by neonatal hyperthyroidism and infant central hypothyroidism. DISCUSSION: This case demonstrates the novel insight that FT due to high fetal thyroid hormone concentrations stimulated by high maternal TRAb levels might also result in (central) hypothyroidism, requiring long-term evaluation of the hypothalamus-pituitary-thyroid axis in these children.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

Iodinated Contrast Induced Hypothyroidism in the Infant After Enteral Contrast Enema: A Case Report and Systematic Review.

Background: Excessive iodine intake triggers the Wolff-Chaikoff effect resulting in downregulation of thyroid hormone synthesis to prevent hyperthyroidism. Failure to escape the Wolff-Chaikoff effect can be seen especially in (premature born) infants and may result in prolonged iodine induced hypothyroidism. We describe a rare case of a preterm infant who developed severe iodinated contrast induced hypothyroidism after the use and prolonged stasis of enteral iodinated contrast media (ICM). In addition a systematic literature search was performed to evaluate all available data on this complication. Methods: A systematic literature search was performed in PubMed and Embase. Studies describing the effect of enteral ICM on thyroid function were considered eligible. The primary outcome was to determine the frequency of contrast induced hypothyroidism in infants after administration of enteral ICM. Results: The premature infant in our center developed severe iodinated contrast induced hypothyroidism after enteral ICM. In total, only two studies met our eligibility data, reporting eight patients. Out of these eight patients, four premature infants developed a contrast induced hypothyroidism after enteral administration of ICM. Conclusion: Data on severity, length and frequency of contrast induced hypothyroidism after exposure to enteral ICM is very scarce. The herein reported case and literature search illustrate the potential severity of the complication and underline the necessity of future studies on this topic. We recommend standardized monitoring of thyroid function after exposure to enteral ICM in newborns to prevent delayed diagnosis of severe contrast induced hypothyroidism until evidence based recommendations can be made.

Variations in volume; Breast size in trans women in relation to timing of testosterone suppression.

CONTEXT: Breast development is an important outcome for trans women receiving gender affirming hormone therapy (GAHT). Limited breast development has been reported, possibly because of testosterone exposure during puberty. The impact of puberty suppression (PS) on breast development is unclear. OBJECTIVE: To investigate the impact of PS and timing of PS prior to GAHT on breast volume and satisfaction. DESIGN: Cross-sectional study. SETTING: Tertiary gender identity clinic. PARTICIPANTS: 60 trans women (aged 17-57 years) after 4.5±1.7 years of GAHT were included of whom 23 initiated PS early in puberty (Tanner stage G2-3), 17 late in puberty (Tanner stage G4-5), and 20 started GAHT in adulthood without prior PS. MAIN OUTCOME MEASURES: Breast volume measured with a 3D scanner and breast satisfaction measured with a questionnaire. Comparisons of breast volumes were adjusted for fat percentage. RESULTS: Median breast volume was 115ml (IQR 68; 203), i.e. bra cup-size

The Definition of Recurrence of Differentiated Thyroid Cancer: A Systematic Review of the Literature.

Background: Recurrence is a key outcome to evaluate the treatment effect of differentiated thyroid carcinoma (DTC). However, no consistent definition of recurrence is available in current literature or international guidelines. Therefore, the primary aim of this systematic review was to delineate the definitions of recurrence of DTC, categorized by total thyroidectomy with radioactive iodine ablation (RAI), total thyroidectomy without RAI and lobectomy, to assess if there is a generally accepted definition among these categories. Methods: This study adhered to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. In December 2023, a systematic literature search in MEDLINE and EMBASE was performed for studies reporting on the recurrence of DTC, from January 2018 to December 2023. Studies that did not provide a definition were excluded. Primary outcome was the definition of recurrence of DTC. Secondary outcome was whether studies differentiated between recurrence and persistent disease. Two independent investigators screened the titles and abstracts, followed by full-text assessment and data extraction. The study protocol was registered in PROSPERO, CRD42021291753. Results: In total, 1450 studies were identified. Seventy studies met the inclusion criteria, including 69 retrospective studies and 1 randomised controlled trial (RCT). Median number of patients in the included studies was 438 (range 25-2297). In total, 17 studies (24.3%) reported on lobectomy, 4 studies (5.7%) on total thyroidectomy without RAI, and 49 studies (70.0%) with RAI. All studies defined recurrence using one or a combination of four diagnostic modalities cytology/pathology, imaging studies, thyroglobulin (-antibodies), and a predetermined minimum tumor-free time span. The most common definition of recurrence following lobectomy was cytology/pathology-proven recurrence (47.1% of this subgroup), following total thyroidectomy with RAI was cytology/pathology-proven recurrence and/or anomalies detected on imaging studies (22.4% of this subgroup). No consistent definition was found following total thyroidectomy without RAI. Nine studies (12.9%) differentiated between recurrence and persistent disease. Conclusion: Our main finding is that there is no universally accepted definition for recurrence of DTC in the current studies across any of the treatment categories. The findings of this study will provide the basis for a future, international Delphi-based proposal to establish a universally accepted definition of recurrence of DTC. A uniform definition could facilitate global discussion and enhance the assessment of treatment outcomes regarding recurrence of DTC.

Age-Specific Reference Intervals for Thyroid-Stimulating Hormones and Free Thyroxine to Optimize Diagnosis of Thyroid Disease.

Background: Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods: This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, and Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2 to 20 years by 2-year categories and decade categories between 20 and 100 years. Results: We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits were higher in early childhood and decreased toward adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onward. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion: This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data are less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

Neonatal screening for primary and central congenital hypothyroidism: is it time to go Dutch?

Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4-TSH-thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.

The role of transducin ß-like 1 X-linked receptor 1 (TBL1XR1) in thyroid hormone metabolism and action in mice.

Transducin ß-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshß and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.

Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism.

OBJECTIVE: The Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. DESIGN & METHODS: NBS data and parameters of CH patients and false-positive referrals in the period 2007-2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. RESULTS: Variables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. CONCLUSIONS: Machine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

A 15-year-old Girl with a Lateral Neck Mass Turning Out to Be Papillary Thyroid Carcinoma-Lateral Ectopic Papillary Thyroid Carcinoma or Lymph Node Metastasis?

Lateral neck lesions in children are common and involve various infectious or inflammatory etiologies as well as embryological remnants such as branchial cleft cysts. Although unusual, ectopic thyroid tissue can also present as a lateral neck mass. Here, we present an unusual case of a 15-year-old girl treated for an asymptomatic lateral neck mass that after surgical removal was found to be papillary thyroid carcinoma (PTC). However, after removal of the thyroid gland, no primary thyroid tumor was found. The question arose whether the lateral neck lesion was a lymph node metastasis without identifiable primary tumor (at histological evaluation) or rather malignant degeneration of ectopic thyroid tissue. Total thyroidectomy was performed with postoperative adjuvant radioactive iodine ablation. Even though PTC in a lateral neck mass without a primary thyroid tumor has been described previously, pediatric cases have not been reported. In this report we share our experience on diagnosis, treatment and follow-up, and review the existing literature.