RESUMO
Autoimmune polyendocrine syndrome type-1 (APS-1) is caused by mono- or biallelic loss-of-function variants of the autoimmune regulator gene AIRE underlying early-onset multiorgan autoimmunity and the production of neutralizing autoantibodies against cytokines, accounting for mucosal candidiasis and viral diseases. Medical intervention is essential to prevent or attenuate autoimmune manifestations. Ruxolitinib is a JAK inhibitor approved for use in several autoimmune conditions. It is also used off-label to treat autoimmune manifestations of a growing range of inborn errors of immunity. We treated three APS-1 patients with ruxolitinib and followed them for at least 30 months. Tolerance was excellent, with no medical or biological adverse events. All three patients had remarkably positive responses to ruxolitinib for alopecia, nail dystrophy, keratitis, mucosal candidiasis, steroid-dependent autoimmune hepatitis, exocrine pancreatic insufficiency, renal potassium wasting, hypoparathyroidism, and diabetes insipidus. JAK inhibitors were therefore considered an effective treatment in three patients with APS-1. Our observations suggest that JAK/STAT pathways are involved in the pathogenesis of APS-1 autoimmune manifestations. They also suggest that JAK inhibitors should be tested in a broader range of APS-1 patients.
Assuntos
Candidíase , Inibidores de Janus Quinases , Poliendocrinopatias Autoimunes , Humanos , Poliendocrinopatias Autoimunes/tratamento farmacológico , Poliendocrinopatias Autoimunes/genética , Autoimunidade , AutoanticorposRESUMO
TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.
Assuntos
Arritmias Cardíacas/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/deficiência , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Transtornos do Neurodesenvolvimento/genética , Rabdomiólise/genética , Adolescente , Criança , Pré-Escolar , Exoma , Feminino , França , Humanos , Hipotireoidismo/genética , Lactente , Masculino , Mitocôndrias/genética , Mutação , Linhagem , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.
Assuntos
Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Disgenesia da Tireoide/genética , Proteínas de Ciclo Celular/biossíntese , Movimento Celular/genética , Exoma/genética , Feminino , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mitose/genética , Linhagem , Disgenesia da Tireoide/patologiaRESUMO
AIM: The aim of this study was to compare genetic (HLA-DQ) and immune markers in a large population of type 1 diabetic (T1D) children and adolescents residing in the same environment, but of different ethnic origin: European Caucasians (EC), Moghrabin Caucasians (MC), Black Africans (BA) and of Mixed Origin (MO). METHODS: Retrospective study, including 452 patients with T1D aged 0.1-17.5 yr at diagnosis recruited at the Diabetology Clinic of the University Children's Hospital Queen Fabiola from May 1995 to March 2013. HLA-DQ genotyping, diabetes-associated autoantibodies, organ-specific autoantibodies, and other markers of autoimmunity were studied. RESULTS: The proportion of the different ethnic groups was: 55% EC, 35% MC, 6% BA, and 4% MO. Between these four groups, there were no significant differences concerning age, hemoglobin A1c (HbA1c), presence of diabetic ketoacidosis, random C-peptide level at diagnosis and 2 yr later. The two most frequent haplotypes were DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 with a significant higher prevalence in MC and EC (p = 0.002 and 0.03, respectively). The high-risk heterozygous genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more frequent in EC than in MC, whereas the homozygous genotype DQA1*0501-DQB1*0201/DQA1*0501-DQB1*0201 was more prevalent in MC (p = 0.019). These susceptible genotypes were more frequent in youngest patients (p = 0.003). Diabetes-associated autoantibodies, organ-specific autoantibodies, and other immune markers did not statistically differ between ethnic groups. CONCLUSIONS: These observations in a large population of T1D children and adolescents of different ethnic groups residing in Belgium show significant differences in HLA-DQ status, but not in diabetes-associated autoantibodies, organ-specific autoantibodies, or other immune markers.
Assuntos
Autoanticorpos , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Adolescente , Bélgica/epidemiologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/etnologia , Feminino , Haplótipos , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.
Assuntos
Índice de Massa Corporal , Craniofaringioma , Neoplasias Hipofisárias , Aumento de Peso , Humanos , Craniofaringioma/epidemiologia , Craniofaringioma/complicações , Aumento de Peso/fisiologia , Masculino , Feminino , Criança , Estudos Retrospectivos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/complicações , Adolescente , Pré-Escolar , Seguimentos , Fatores de Risco , Hipotálamo , Estudos de CoortesRESUMO
BACKGROUND: While the risk for hypoglycemia during acute illness is well described in children with classical congenital adrenal hyperplasia (CAH), there is little evidence for the prevalence of asymptomatic hypoglycemia and the daily glucose patterns in CAH. Herein, we explored the daytime glucose profile of children with classical CAH. METHODS: We conducted an observational study in 11 children (6 female; age 3.1 years [1.4, 5.1]; body mass index 17.3â kg/m2 [15.6, 17.9]) with a genetic diagnosis of classical CAH receiving hydrocortisone and fludrocortisone replacement therapy. Participants underwent 2 14-day continuous glucose monitoring (CGM) sessions and an inpatient 24â h series cortisol and adrenocorticotropic hormone (ACTH) measures. Data were analyzed for 3 daytime lags (7 Am-4 Pm, 4 Pm-10pm, 10 Pm-7 Am) corresponding to the hydrocortisone dosing period with cortisol and ACTH measured before the hydrocortisone dose. RESULTS: Eleven participants completed at least 1 CGM session, and 7 out of 11 underwent both the CGM session and the cortisol/ACTH serial measures. In the whole cohort, the percentage of time of sensor glucose values <70â mg/dL was higher during the 10 Pm-7 Am and the 7 Am-4 Pm time slots than in the late afternoon period (17% [7, 54] and 15% [6.8, 24] vs 2% [1.1, 16.7] during the periods 7 Am-4 Pm and 4 Pm-10 Pm, respectively [P = .006 and P = .003]). Nighttime hypoglycemia was mostly spent below the 65â mg/dL (10.9% [4.1, 34]). The glycemic pattern paralleled the nadir of daily cortisol at 7 Am (10.3±4.4â µg/dL). A greater percentage of time in hypoglycemia was associated with lower cortisol concentration at 7 Am and 10 Pm (P < .001 and P = .005). CONCLUSIONS: Continuous glucose monitoring demonstrated a disrupted daily glucose pattern in children with CAH, paralleled by a lower cortisol concentration. CLINICALTRIALS.GOV REGISTRATION: NCT04322435.
Assuntos
Hiperplasia Suprarrenal Congênita , Hipoglicemia , Criança , Feminino , Humanos , Pré-Escolar , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Hidrocortisona , Glucose , Automonitorização da Glicemia , Glicemia , Hormônio AdrenocorticotrópicoRESUMO
Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.
Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Adulto , Criança , Humanos , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamento farmacológico , Estudos RetrospectivosRESUMO
Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. Methods: We characterized thyroid development and function in Borealin-deficient (Borealin +/-) mice using histology, transcriptomic analysis, and quantitative PCR. Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin +/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin +/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin +/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Neoplasias da Glândula Tireoide , Animais , Camundongos , Proteínas de Ciclo Celular/genética , Hipotireoidismo Congênito/genética , Câncer Papilífero da Tireoide/genética , Disgenesia da Tireoide/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
CONTEXT: Craniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma. OBJECTIVE: To evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence). METHODS: Retrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (<12-month group), among which 29 patients were treated between 6 and 12 months (6-12 month group). The main outcome was the risk of tumor new event (progression of residual tumor or tumor recurrence after complete resection) after primary treatment in the >12-month group and in the <12 month or in the 6- to 12-month group patients. RESULTS: In the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the <12-month group. The 2- and 5-year event-free survivals were the same in the 6- to 12-month group (72.4%; 95% CI, 52.4-85.1). By log-rank test, the event-free survival was not different between groups (P = .98 and P = .91).The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment. CONCLUSIONS: No association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.
Assuntos
Craniofaringioma , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Humanos , Criança , Craniofaringioma/patologia , Estudos Retrospectivos , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Recidiva Local de Neoplasia/etiologia , Hormônio do Crescimento Humano/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversosRESUMO
Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). DH accounts for about 35% of CH and a genetic cause is identified in 50% of patients. However, TD accounts for about 65% of CH, and a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development and function. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.
Title: Génétique de l'hypothyroïdie congénitale. Abstract: L'hypothyroïdie congénitale (HC) est la maladie endocrinienne néonatale la plus fréquente. Elle peut être due à des défauts de développement ou de la fonction de la thyroïde (HC primaire ou périphérique) ou d'origine hypothalamo-hypophysaire (HC centrale). L'HC primaire est causée dans la majorité des cas par une anomalie du développement de la glande (dysgénésie thyroïdienne, DT) ou par un défaut de synthèse des hormones thyroïdiennes (dyshormonogenèse, DH). Une origine génétique est identifiée chez 50 % des patients présentant une HCDH mais dans moins de 5 % des patients présentant une HCDT. Cette revue fait le point sur l'ensemble des causes génétiques des HC et sur les différents modes de transmission. L'HC n'est plus simplement une maladie dominante pour les dysgénésies thyroïdiennes et récessive pour les dyshormonogenèses, mais est devenue une maladie plus complexe.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Hipotireoidismo Congênito/genética , Bases de Dados Genéticas , Humanos , Mutação , Disgenesia da Tireoide/genética , Hormônios TireóideosRESUMO
Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.
RESUMO
Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and the most common preventable cause of development delay and growth failure if diagnosed and treated early. The thyroid is the first endocrine gland to develop during embryonic life and to be recognizable in humans. Thyroid development and maturation can be divided into 2 phases: a first phase of embryogenesis and a second phase of folliculogenesis and differentiation with thyroid hormone production at the final steps. Regulation of the thyroid function requires normal development of the hypothalamic-pituitary-thyroid axis, which occurs during the embryonic and neonatal period. Defects in any of steps of thyroid development, differentiation, and regulation lead to permanent CH. Newborn screening programs, established in only one-third of countries worldwide, detect CH and are cost-effective and highly sensitive and specific. During the last decade, epidemiology of CH has changed with increased frequency of thyroid in situ in primary CH. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. However, a molecular cause is identified in only 5% of CH due to thyroid dysgenesis. The purpose of this article is to describe the clinical approach to the child with CH, focusing on diagnostic work-up and future challenges on optimizing thyroid replacement therapy and regenerative medicine. The review is written from the perspective of the case of 2 girls referred for CH after newborn screening and diagnosed with thyroid ectopy. The genetic work-up revealed novel mutations in TUBB1 gene, associated with large platelets and abnormal platelet physiology.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Criança , Feminino , Humanos , Recém-Nascido , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/terapia , Triagem Neonatal , Disgenesia da Tireoide/complicações , Hormônios TireóideosRESUMO
The SFE-AFCE-SFMN 2022 consensus deals with the management of thyroid nodules, a condition that is a frequent reason for consultation in endocrinology. In more than 90% of cases, patients are euthyroid, with benign non-progressive nodules that do not warrant specific treatment. The clinician's objective is to detect malignant thyroid nodules at risk of recurrence and death, toxic nodules responsible for hyperthyroidism or compressive nodules warranting treatment. The diagnosis and treatment of thyroid nodules requires close collaboration between endocrinologists, nuclear medicine physicians and surgeons, but also involves other specialists. Therefore, this consensus statement was established jointly by 3 societies: the French Society of Endocrinology (SFE), French Association of Endocrine Surgery (AFCE) and French Society of Nuclear Medicine (SFMN); the various working groups included experts from other specialties (pathologists, radiologists, pediatricians, biologists, etc.). The present section deals with the specific aspects of the management of euthyroid nodules in patients under 18 years of age.
Assuntos
Endocrinologia , Medicina Nuclear , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Criança , Adolescente , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/terapia , Nódulo da Glândula Tireoide/patologia , Cintilografia , Consenso , Neoplasias da Glândula Tireoide/patologiaRESUMO
CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.
Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Transportadores de Ácidos Monocarboxílicos/deficiência , Hipotonia Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Simportadores/deficiência , Tri-Iodotironina/análogos & derivados , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/genética , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/sangue , Hipotonia Muscular/genética , Atrofia Muscular/sangue , Atrofia Muscular/genética , Mutação , Estudos Retrospectivos , Simportadores/genética , Resultado do Tratamento , Tri-Iodotironina/administração & dosagem , Tri-Iodotironina/efeitos adversos , Tri-Iodotironina/sangue , Adulto JovemRESUMO
INTRODUCTION: Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients. PURPOSE: The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways. RESULTS AND CONCLUSION: We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.
Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Hipotireoidismo Congênito/genética , Bases de Dados Genéticas , Humanos , Recém-Nascido , Mutação , Disgenesia da Tireoide/genética , Hormônios TireóideosRESUMO
Background: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.
Assuntos
Hipotireoidismo Congênito/terapia , Endocrinologia/normas , Benchmarking/normas , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/epidemiologia , Consenso , Medicina Baseada em Evidências/normas , Humanos , Recém-Nascido , Triagem Neonatal/normas , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Transição para Assistência do Adulto/normasRESUMO
BACKGROUND: Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2. PATIENT: In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes. CONCLUSIONS: We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.
Assuntos
Hipotireoidismo Congênito/genética , Bócio/genética , Mutação , Simportadores/genética , Adolescente , Criança , Pré-Escolar , Hipotireoidismo Congênito/tratamento farmacológico , Bócio/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Diagnóstico Pré-Natal , Tiroxina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Assuntos
Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hipotireoidismo Congênito/fisiopatologia , Oxidases Duais/genética , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Linhagem , Simportadores/genética , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Adulto JovemRESUMO
BACKGROUND: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T3) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T3 analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency. METHODS: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 µg Triac, the daily dose was increased progressively in 350 µg increments, with the goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T3 concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and total reverse T3 from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with ClinicalTrials.gov, number NCT02060474. FINDINGS: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 µg/kg of bodyweight (range 6·4-84·3) to attain T3 concentrations within the target range. Serum T3 concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T4 concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T4 concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T3 by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment. INTERPRETATION: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. FUNDING: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.
Assuntos
Proteínas de Membrana Transportadoras/administração & dosagem , Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Hipotonia Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Tri-Iodotironina/análogos & derivados , Adolescente , Criança , Pré-Escolar , Europa (Continente) , Seguimentos , Guias como Assunto , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras/farmacologia , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Hipotonia Muscular/fisiopatologia , Atrofia Muscular/fisiopatologia , Segurança do Paciente , África do Sul , Tri-Iodotironina/administração & dosagem , Tri-Iodotironina/farmacologia , Adulto JovemRESUMO
BACKGROUND: Primary congenital hypothyroidism (CH) affects about 1:3000 newborns worldwide and is mainly caused by defects in thyroid gland development (thyroid dysgenesis [TD]) or hormone synthesis. A genetic cause is identified in <10% of TD patients. The aim was to identify novel candidate genes in patients with TD using next-generation sequencing tools. PATIENT FINDINGS: Whole exome sequencing was used to study two families: a consanguineous Tunisian family (one child with severe thyroid hypoplasia) and a French family (two newborn siblings, with a thyroid in situ that was not enlarged on ultrasound at diagnosis). Variants in candidate genes were filtered according to type of variation, frequency in public and in-house databases, in silico prediction tools, and inheritance mode. Unexpectedly, three different variants of the thyroid peroxidase (TPO) gene were identified. A homozygous missense mutation (c.875C>T, p.S292F) was found in the Tunisian patient with severe thyroid hypoplasia. The two French siblings were compound heterozygotes (c.387delC/c.2578G>A, p.N129Kfs*80/p.G860R) for TPO mutations. All three mutations have been previously described in patients with goitrous CH. In these patients, treatment was initiated immediately after diagnosis, and the effect, if any, of thyrotropin stimulation of these thyroids remains unclear. CONCLUSIONS: The first cases are reported of thyroid hypoplasia at diagnosis during the neonatal period in patients with CH and TPO mutations. These cases highlight the importance of screening for TPO mutations not only in goitrous CH, but also in normal or small-size thyroids, and they broaden the clinical spectrum of described phenotypes.