Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

TSHRV656F Activating Variant of the Thyroid Stimulating Hormone Receptor Gene in Neonatal Onset Hyperthyroidism: A Case Review

An activating variant of the thyroid stimulating hormone receptor (TSHR) gene is one of the rare causes of neonatal hyperthyroidism. This disorder may occur as a result of an autosomal dominant inheritance or sporadically through de novo variation. Here we present a case of neonatal onset congenital non-autoimmune hyperthyroidism (NAH) with a sporadic germline activating TSHRV656F variant. A female infant with tachycardia, who was transferred due to hyperthyroidism in the first week of life, displayed no other symptoms or signs. The patient's mother did not have Graves' disease, and TSHR stimulating antibodies were not present in the mother or baby. Imaging showed thyroid gland hyperplasia and left ventricular hypertrophy, the patient was subsequently put on methimazole treatment. After six months undergoing treatment, a heterozygous p.Val656Phe (V656F) (c.1966G>T) variant was detected on exon 10 of the TSHR gene. The variant was not identified in the mother and father, so the case was assumed to be sporadic. In conclusion, although the literature describes V656F variant as a somatic variant in children and adults with toxic thyroid nodule(s) that results in the structural activation of the TSH receptor, no previous cases of neonatal hyperthyroidism due to TSHRV656F variant have been reported. This study is the first case review that highlights the relationship between TSHRV656F variant and neonatal onset NAH.

[Characterization of children born to mothers with Graves' disease]. / Caracterización de recién nacidos hijos de madres portadoras de enfermedad de Graves.

INTRODUCTION: Neonatal hyperthyroidism is a disease that can cause mortality and sequelae. To date, there is no clinical series of cases that allows us to know the local reality of this condition. OBJECTIVE: to charac terize the children of mothers with Graves' disease (GD) from a clinical and biochemical point of view. SUBJECTS AND METHOD: A prospective follow-up of all newborns (NB) of mothers with history of GD was performed in two public hospitals in Santiago, during 5 years. Clinical and laboratory variables of mother-child pairs and thyroid-stimulating hormone receptor antibodies (TRAbs) le vels were analyzed looking for associations between these variables and the development of neonatal hyperthyroidism. RESULTS: Seventy-six mother-child pairs were included (0.2% of all deliveries). Five neonates (6.6%) presented biochemical hyperthyroidism, and 3 of them developed clinical disease and required treatment. All 5 NBs who developed hyperthyroidism had mothers with positive or indeterminate TRAbs. No child of TRAbs-negative mothers developed the disease. TRAbs could be determined in only 65% of the mothers and 72% of the NBs. There was a significant correlation bet ween maternal TRAbs titers (p < 0.03), neonatal TRAbs titers (p < 0.008), and neonatal TSH between days 2-6 (p < 0.006), with the subsequent development of hyperthyroidism. All cases of neonatal hyperthyroidism were transient. There was no mortality in our series. CONCLUSIONS: This is the first national case series of children of mothers with GD. Maternal and neonatal TRAbs and TSH between days 2-6 of life were predictors of neonatal hyperthyroidism.

Prevalence and course of thyroid dysfunction in neonates at high risk of Graves' disease or with non-autoimmune hyperthyroidism.

OBJECTIVE: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD). DESIGN AND METHODS: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder. RESULTS: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4). CONCLUSION: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

Familial neonatal nonautoimmune hyperthyroidism due to a gain-of-function (D619G) thyrotropin-receptor mutation.

OBJECTIVES: Activating germline mutations of the thyroid-stimulating hormone receptor (TSHR) are responsible for a rare form of neonatal nonautoimmune hyperthyroidism (NAH). We report the first case of familial neonatal neonatal nonautoimmune associated with c.1856A>G (p.Asp619Gly) variant in the TSHR gene. CASE PRESENTATION: We describe an eight-year-old African-American female presenting with neonatal NAH associated with an inherited heterozygous c.1856A>G (p.Asp619Gly) variant in the TSHR gene. This variant was previously described in one patient presenting with sporadic NAH in adolescence. Our patient was diagnosed with hyperthyroidism in the neonatal period. The mother had a history of hyperthyroidism and had thyroidectomy at the age of 4 years. The patient had goiter and elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels that normalized with methimazole treatment; however, TSH level remained suppressed. Thyroid antibodies were negative. The patient also had bilateral exotropia, a trait shared by the mother and may represent a new association. CONCLUSIONS: Familial neonatal NAH is associated with heterozygous c.1856A>G (p.Asp619Gly) variant of the TSHR gene.

Nonautoimmune Hyperthyroidism Caused by a Somatic Mosaic GNAS Mutation Involving Part of the Thyroid Gland.

Nonautoimmune hyperthyroidism caused by activating mutations in the GNAS gene is a rare condition. In this study, we report a five-year-old girl diagnosed with nonautoimmune hyperthyroidism and tall stature harboring a somatic mosaic gain-of-function mutation in the GNAS gene (NM_080425.3: c.2530C>T;p.Arg844Cys previously reported as NM_000516.5:c.601C>T;p.Arg201Cys) and referred to thereafter as R201C, in three of four quadrants of the thyroid gland. Provision of a molecular diagnosis may avoid unnecessary complete ablation of the thyroid gland.

Hypothyroidism and hyperthyroidism.

Congenital hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormones. It occurs in 1:2000-4000 newborns. Common clinical features include decreased activity and increased sleep, feeding difficulty, constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment, congenital hypothyroidism leads to severe intellectual deficit and short stature. Congenital hyperthyroidism occurs when the thyroid gland produces too much of the hormone thyroxine, which can accelerate body metabolism, causing unintentional weight loss and a rapid or irregular heartbeat. Hyperthyroidism is very rare and its prevalence is unknown. Common clinical features include unintentional weight loss, tachycardia, arrhythmia, palpitations, anxiety, tremor and sweating. Here we summarize the genes involved in congenital hypo- and hyperthyroidism and the tests we use for genetic analysis.

Congenital Hypothyroidism: 8-Year Experience Using 2 Newborn Screens in Alabama.

BACKGROUND/AIMS: Newborn screening protocols for congenital hypothyroidism (CH) vary as to whether a TSH or T4 algorithm or some combination is performed. We aimed to determine the 3-year clinical outcome of infants diagnosed with CH and screen-positive for CH using a 2-screen protocol that measures both T4 and TSH on all specimens. METHODS: Retrospective analysis of patients with CH who were detected by first (NBS1) or second (NBS2) newborn screen in Alabama (2009-2016) and followed at our university-based practice. Clinical follow-up established the final diagnoses in 146 patients, including a subset of 72 patients with eutopic glands. RESULTS: 168 patients were studied: 139 (83%) were detected by NBS1 and 29 (17%) by NBS2. Screening T4 concentrations were 45% reduced in NBS2 compared to NBS1 (p= 0.0002). Thyroid dysgenesis was present in 55% of NBS1 patients while all in NBS2 were eutopic. Follow-up of 146 patients confirmed permanent CH in 92 patients in NBS1 (75%) and 5 in NBS2 (20%). Hispanic infants were only detected by NBS1, and 93% had permanent CH. Transient CH was associated with congenital heart disease. In patients with eutopic, permanent CH, dyshormonogenesis was confirmed in 23% of NBS1 patients and 40% of NBS2. One case of central CH was detected by each screen. CONCLUSIONS: This 8-year, retrospective study buttresses the importance of a 2-screen approach for CH by identifying 5 infants with clinically significant permanent thyroid dysfunction including dyshormonogenesis and central hypothyroidism. It is the first 2-screen study to incorporate thyroid ultrasound. Disconcertingly, 4 of 5 second-screen infants with permanent CH had no risk factors for CH, and these infants would otherwise not have been detected.

Screening of congenital hyperthyroidism in Morocco: a pilot study.

BACKGROUND: In Morocco we have no reliable information on the incidence of congenital hypothyroidism (HC). AIMS: The aim of our study was to explore the feasibility of a neonatal screening program for this disease in Morocco. METHODS: We conducted a screening campaign in the HC 15 615 newborns in the wilaya of Fez in north-central Morocco. Positive cases have been followed up during seven years. Over the same period, we conducted a retrospective qualitative study among parents of newly screened positive newborns and health professionals. RESULTS: Twelve cases of hypothyroidism have been confirmed, a frequency 1p1301 births. When excluding 4 cases of hypothyroidism transients, the frequency of HC becomes 1p1952 births, athyreosis represents 25% of cases, partial agenesis 25% of cases and 50 % of cases had normal thyroid glands in place; 67% are female and 33% male. The average age of testing was 17.1 ± 6.6 days and the start of treatment was 43.4 ± 8.7 days. Tracking cases brought under replacement therapy showed a good evolution of anthropometric parameters and psychomotor. The qualitative study found that parents are monitoring their babies very seriously despite the very low socio-economic class of the vast majority of them. CONCLUSIONS: The results of our study support the need for the establishment of a neonatal screening programme for congenital hypothyroidism in Morocco.

Utility of systematic TSHR gene testing in adults with hyperthyroidism lacking overt autoimmunity and diffuse uptake on thyroid scintigraphy.

OBJECTIVE: Patients with hyperthyroidism lacking autoimmune features but showing diffuse uptake on thyroid scintigram can have either Graves' disease or germline activating TSH receptor (TSHR) mutation. It is important to identify patients with activating TSHR mutation due to treatment implication, but the overlapping clinical features with Graves' disease make it difficult to discriminate these two conditions without genetic testing. Our study aimed to assess the potential of systematic TSHR mutation screening in adults with hyperthyroidism, showing diffuse uptake on thyroid scintigraphy but absence of TSH receptor antibodies (TRAb) and clinical signs of autoimmunity. DESIGN: A cross-sectional study of Caucasian adults with hyperthyroidism, managed at three endocrine centres in the South West, UK, from January 2006 to April 2017. METHODS: We recruited 78 adult Caucasian patients with hyperthyroidism showing diffuse uptake on 99m Tc-pertechnetate thyroid scintigraphy but without TRAb and other autoimmune clinical features of Graves' disease (such as thyroid-associated ophthalmopathy or dermopathy). Genomic DNA of these patients was analysed for variants in the TSHR gene. RESULTS: Genetic analysis identified 11 patients with four variants in TSHR [p.(Glu34Lys), p.(Asp36His), p.(Pro52Thr) and p.(Ile334Thr)]. None of these variants were pathogenic according to the American College of Medical Genetics and Genomics guideline. CONCLUSIONS: Activating TSHR mutations are a rare cause of nonautoimmune adult hyperthyroidism. Our study does not support the routine genetic testing in adult patients with hyperthyroidism showing diffuse uptake on scintigraphy but negative TRAb and lacking extrathyroidal manifestations of Graves' disease.

Incidence of Neonatal Hyperthyroidism Among Newborns of Graves' Disease Patients Treated with Radioiodine Therapy.

BACKGROUND: The serum thyrotropin receptor antibody (TRAb) titers of Graves' disease (GD) patients are known to increase after radioiodine (RAI) therapy, and they can remain high for years. The incidence of neonatal hyperthyroidism (NH) among newborns of mothers with GD who conceived after RAI therapy has not been previously reported. The aims of this study were to investigate the incidence of NH among newborns of mothers who conceived within two years after RAI therapy, and to identify predictors of NH. METHODS: GD patients (n = 145) who conceived within two years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected. RESULTS: Of the 145 pregnant women, 54 (37%) were treated with antithyroid drugs or potassium iodide for maternal hyperthyroidism during the first trimester. There were eight newborns with NH, resulting in an incidence of 5.5%. Seven of the eight mothers whose newborns had NH were treated with antithyroid drugs or potassium iodide during their pregnancy. The incidence of NH among the newborns of mothers who conceived within 6-12 months after RAI therapy was 8.8%, within 12-18 months was 5.5%, and within 18-24 months was 3.6%. Multivariate analysis revealed that the TRAb values in the third trimester were the only risk factor for NH. The cutoff TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference value <2.0 IU/L). CONCLUSIONS: The incidence of NH among newborns of mothers who conceived within two years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose TRAb value is high in the third trimester should be carefully followed by an obstetrician during pregnancy, and the newborns should be carefully followed by a pediatrician after birth.

Hijos de madres con enfermedad de Basedow Graves / Newborn of mothers with Graves' disease

Resumen: Introducción: La causa más frecuente de hipertiroidismo congénito es la enfermedad de Basedow Graves (EG) materna, en la que anticuerpos anti receptor de hormona tiroestimulante (TSH) (TRAb) atraviesan la placenta estimulando al receptor de TSH fetal y/o neonatal para producir hormonas ti roideas. La disfunción tiroidea en estos pacientes se confirma con el aumento de las concentraciones de tiroxina (T4) y triyodotironina (T3) acompañado de niveles de TSH suprimida. Objetivos: Carac terizar la evolución clínica y bioquímica de los recién nacidos (RN) hijos de madres con EG, y sugerir recomendaciones respecto al tratamiento y seguimiento. Material y Método: Se realizó una revisión de la literatura usando la base de datos MEDLINE, identificando artículos que incluyeran más de 30 RN de madres con EG y describieran su evolución. Se agregaron además revisiones del tema enfati zando la evaluación y manejo de los hijos de madres con EG. Resultados: Se incluyeron 9 estudios de cohorte que incorporaron 790 embarazadas. Hubo heterogeneidad entre los trabajos; un porcentaje variable de los hijos desarrolló tirotoxicosis neonatal, la que fue más frecuente cuando las madres presentaron concentraciones elevadas de TRAb. El tratamiento de los RN se inició según diferentes criterios. La literatura recomienda tratar los casos de hipertiroidismo clínico y considerarlo en casos de hipertiroidismo bioquímico. Conclusión: Los hijos de madres con EG y TRAb elevados deben ser evaluados por la probabilidad de desarrollar tirotoxicosis neonatal. Se sugiere controlar función tiroidea periódicamente durante el primer mes de vida y tratar los pacientes con hipertiroidismo clínico y bioquímico.

Abstract: Introduction: The most frequent cause of congenital hyperthyroidism is maternal Graves' disease (GD), in which thyroid stimulating hormone (TSH) receptor antibodies (TRAb) cross the placenta and stimulate the fetal and/or neonatal TSH receptor to produce thyroid hormones. Thyroid dys function in these patients is confirmed by increased thyroxine (T4) and triiodothyronine (T3) levels accompanied by suppressed TSH levels. Objective: To characterize the clinical and biochemical evo lution of newborns of mothers with GD and to suggest recommendations regarding treatment and follow-up. Material and Method: A literature review using the MEDLINE database was made, iden tifying scientific articles that included more than 30 neonates of mothers with GD and described their evolution. In addition, a review of the topic with an emphasis on the evaluation and management of these patients was included. Results: Nine cohort studies were included, with a total of 790 pregnant women. There was high heterogeneity among the studies. A variable percentage of newborns deve loped neonatal thyrotoxicosis, which was more frequent in those patients whose mothers had high levels of TRAb. The treatment of newborns was initiated according to different criteria. The literature recommends treating cases of clinical hyperthyroidism and considers it in cases of biochemical hy perthyroidism. Conclusion: Children of mothers with GD and high TRAb should be evaluated due to the likelihood of developing neonatal thyrotoxicosis. It is suggested to monitor thyroid function periodically during the first month of life and treat patients with clinical and biochemical hyper thyroidism.

[Newborn of mothers with Graves' disease]. / Hijos de madres con enfermedad de Basedow Graves.

INTRODUCTION: The most frequent cause of congenital hyperthyroidism is maternal Graves' disease (GD), in which thyroid stimulating hormone (TSH) receptor antibodies (TRAb) cross the placenta and stimulate the fetal and/or neonatal TSH receptor to produce thyroid hormones. Thyroid dys function in these patients is confirmed by increased thyroxine (T4) and triiodothyronine (T3) levels accompanied by suppressed TSH levels. OBJECTIVE: To characterize the clinical and biochemical evo lution of newborns of mothers with GD and to suggest recommendations regarding treatment and follow-up. MATERIAL AND METHOD: A literature review using the MEDLINE database was made, iden tifying scientific articles that included more than 30 neonates of mothers with GD and described their evolution. In addition, a review of the topic with an emphasis on the evaluation and management of these patients was included. RESULTS: Nine cohort studies were included, with a total of 790 pregnant women. There was high heterogeneity among the studies. A variable percentage of newborns deve loped neonatal thyrotoxicosis, which was more frequent in those patients whose mothers had high levels of TRAb. The treatment of newborns was initiated according to different criteria. The literature recommends treating cases of clinical hyperthyroidism and considers it in cases of biochemical hy perthyroidism. CONCLUSION: Children of mothers with GD and high TRAb should be evaluated due to the likelihood of developing neonatal thyrotoxicosis. It is suggested to monitor thyroid function periodically during the first month of life and treat patients with clinical and biochemical hyper thyroidism.

Excesso de tiroxina materna associado ao hipertireoidismo pós-natal reduz o crescimento ósseo e o perfil proliferativo e angiogênico das cartilagens de crescimento de ratos / Excess maternal thyroxine associated with postnatal hyperthyroidism reduces bone growth and proliferative and angiogenic profile of rats growth cartilage

Foram estudados os efeitos do excesso da tiroxina materna associado ao hipertireoidismo pós-natal sobre o crescimento ósseo e o perfil proliferativo e angiogênico das cartilagens. Dezesseis ratas Wistar adultas foram distribuídas nos grupos tratados com L-tiroxina e controle. A prole do grupo tratado recebeu L-tiroxina do desmame até 40 dias de idade. Ao desmame, foi realizada dosagem plasmática de T4 livre nas mães. Na prole, foram realizados: dosagem plasmática de T3 total e T4 livre, morfometria das tireoides, mensuração do comprimento e largura do fêmur. Nas cartilagens, foi avaliada a expressão imuno-histoquímica e gênica de CDC-47, VEGF, Flk-1, Ang1, Ang2 e Tie2. As médias entre grupos foram comparadas pelo teste T de Student. As concentrações de T4 livre das mães tratadas e de T3 total e T4 livre da prole foram significativamente mais elevadas. A largura do fêmur foi menor nos animais tratados. Houve também redução da imunoexpressão de CDC-47 e de VEGF e dos transcritos gênicos para VEGF e Ang1 nas cartilagens. Conclui-se que o excesso de tiroxina materna associado ao hipertireoidismo pós-natal reduz a largura da diáfise femoral, a proliferação celular e a expressão de VEGF e de Ang1 nas cartilagens de crescimento de ratos.(AU)

The effects of excess of maternal thyroxine associated with postnatal hyperthyroidism at bone growth and proliferative and angiogenic profile of cartilage were studied. Sixteen adult Wistar rats were divided into treated and control groups. The offspring of the treated group received L-thyroxine from weaning to 40 days-old. At weaning, plasma assay of free T4 was measurement on female rats. In the offspring, the following assessments were performed: measurement of total T3 and free T4, histomorphometry analysis of the thyroid, measurement of body weight and length and width of the femur. In femoral growth cartilage, immunostaining of CDC-47, gene or protein expression of VEGF, Flk-1, Ang1, Ang2 and Tie2 were evaluated. Data were analyzed using Student's t-test. Free T4 was significantly higher in treated rats and total T3 and free T4 were significantly higher in offspring. The width of the femur was significantly lower in treated animals. There was lower immunoreactivity of CDC-47, VEGF and lower expression of gene transcripts for VEGF and Ang1. We concluded that the excess maternal thyroxine associated with postnatal hyperthyroidism reduces the width of the femoral shaft, the cell proliferation and gene and protein expression of VEGF and gene expression of Ang1 on the growth cartilage in rats.(AU)

Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism.

BACKGROUND: Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. METHODS: Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. RESULTS: Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. CONCLUSIONS: The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

Hyperplasia in glands with hormone excess.

Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.

Transient neonatal hyperthyrotropinemia is a risk factor for developing persistent hyperthyrotropinemia in childhood with repercussion on developmental status.

OBJECTIVE: Transient neonatal hyperthyrotropinemia (TNH) is defined as a neonatal abnormality of thyroid function, which reverts to normal at re-examination after 2 weeks of life. The thyroid function of these infants has not been sufficiently studied in terms of the risk of developing persistent hyperthyrotropinemia (PH) in later childhood and its impact on growth and development. DESIGN: A prospective cohort study included all babies born in our hospital between 2001 and 2006 and screened for hypothyroidism, whose thyroid function was re-examined 6 years later. Exclusion criteria included the following conditions: preterm birth, birth weight <2500 g, Down's syndrome, descendants of mothers with immune thyroid disease, congenital malformations, cardiac, renal, hepatic, and metabolic diseases, and steroid or dopamine medication. The variables included are TSH and thyroxine at neonatal screening and 6 years later. Main outcomes are the risk of developing PH in childhood, linear growth, and development using Parents' Evaluation of Developmental Status (PEDS). RESULTS: Out of 5040 normal-term newborns, 301 (6.0%, 95% CI 5.3-6.6%) have TSH ≥10 mU/l (TNH). Six years later, we re-examined 65 randomly selected children with TNH and 185 controls. In the TNH cohort, we found six out of 65 children (9.2%, 95% CI 1.4-17.0%) with PH (TSH ≥6.4 mU/l), and three out of 185 (1.6%, 95% CI 0.3-4.7%) among controls, relative risk 5.7 (95% CI 1.5-22.1), P=0.0114. TSH and developmental delay were found to be significantly higher in the TNH cohort (4.7±1.3 mU/l vs 2.1±0.5 mU/l, P<0.0001 and 15/65 (23%, 95% CI 12-34.1) vs 21/185 (11.3%, 95% CI 6.5-16.2) P=0.0348). CONCLUSIONS: Newborns with TNH have a higher risk of developing PH in childhood, with repercussion on developmental status.

A newly discovered TSHR variant (L665F) associated with nonautoimmune hyperthyroidism in an Austrian family induces constitutive TSHR activation by steric repulsion between TM1 and TM7.

OBJECTIVE: New in vivo mutations in G protein-coupled receptors open opportunities for insights into the mechanism of receptor activation. Here we describe the molecular mechanism of constitutive TSH receptor (TSHR) activation in an Austrian family with three generations of familial nonautoimmune hyperthyroidism. PATIENTS: The index patient was diagnosed with hyperthyroidism during her first pregnancy. Her first two children were diagnosed with hyperthyroidism at the age of 11 and 10 years, respectively. TSH suppression was also observed in the third child at the age of 8 years, who has normal free T4 levels until now. TSH suppression in infancy was observed in the fourth child. The mother of the index patient was diagnosed with toxic multinodular goiter at the age of 36 years. METHODS: DNA was extracted from blood samples from the index patient, her mother, and her four children. Screening for TSHR mutations was performed by high-resolution melting assays and subsequent sequencing. Elucidation of the underlying mechanism of TSHR activation was carried out by generation and structural analysis of TSHR transmembrane homology models and verification of model predictions by functional characterization of receptor mutations. RESULTS AND CONCLUSIONS: A newly discovered TSHR mutation L665F in transmembrane helix 7 of the receptor was detected in six members of this family. Functional characterization of L665F revealed constitutive activation for the Gs pathway and thus represents the molecular cause for hyperthyroidism in this family. The constitutive activation is possibly linked to a steric clash introduced by the L665F mutation between transmembrane helices 1 and 7.