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BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated. OBJECTIVES: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD. METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers. RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging. CONCLUSION: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.
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Hipotiroidismo Congénito , Factor Nuclear Tiroideo 1 , Humanos , Recién Nacido , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/sangre , Tamizaje Neonatal/métodos , Pruebas de Función de la Tiroides , Glándula Tiroides/metabolismo , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/patología , Factor Nuclear Tiroideo 1/genética , Factor Nuclear Tiroideo 1/metabolismo , Tirotropina/sangreRESUMEN
Managing patients unable to produce sex steroids using gonadotropins to mimic minipuberty in hypogonadotropic hypogonadism, or sex steroids in patients with Klinefelter or Turner syndrome, is promising. There is a need to pursue research in this area, with large prospective cohorts and long-term data before these treatments can be routinely considered.
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Hipogonadismo , Síndrome de Klinefelter , Síndrome de Turner , Humanos , Síndrome de Turner/tratamiento farmacológico , Síndrome de Turner/complicaciones , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/etiología , Síndrome de Klinefelter/complicaciones , Síndrome de Klinefelter/tratamiento farmacológico , Lactante , Masculino , Preescolar , Femenino , Terapia de Reemplazo de Hormonas/métodos , Niño , Gonadotropinas/uso terapéuticoRESUMEN
Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.
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Hormona de Crecimiento Humana , Hipopituitarismo , Adulto , Niño , Recién Nacido , Humanos , Hibridación Genómica Comparativa , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Hipopituitarismo/terapia , Hipófisis/patología , Hormona AdrenocorticotrópicaRESUMEN
Objective: Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to compare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates. Design: Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019. Methods: Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses. Results: Thirty-five patients were included. A significantly higher increase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)). Conclusions: Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferation, and testicular descent, with both treatment modalities.
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BACKGROUND: NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet. METHODS AND ANALYSIS: This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022). DISCUSSION: This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions.
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Investigación Biomédica , Cuidadores , Humanos , Europa (Continente) , Investigación Cualitativa , EspañaRESUMEN
Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.
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Linfocitos B , Vacunas contra la COVID-19 , COVID-19 , Interferón Tipo I , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Autoanticuerpos , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Receptor Toll-Like 7/genética , Vacunación , Vacunas de ARNm , Vacunas contra la COVID-19/inmunología , Linfocitos B/inmunología , Interferón Tipo I/deficienciaRESUMEN
INTRODUCTION: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation. METHODS: We retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min-max). RESULTS: Clinical symptoms at diagnosis (age, 1.5 [0.5-8.7] years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 [1.40-2.40] mmol/L), hypophosphatemia (-3.4 [-13.4 to (-)0.2] SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 [521-7000] IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% [11/19]). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence. CONCLUSION: Overall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.
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Raquitismo Hipofosfatémico Familiar , Raquitismo , Humanos , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/uso terapéutico , Estudios Retrospectivos , Raquitismo/genética , Raquitismo Hipofosfatémico Familiar/diagnóstico , Vitamina D/uso terapéutico , Fenotipo , GenotipoRESUMEN
Introduction: A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective: This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods: Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results: A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions: In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement: About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.
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Gonadoblastoma , Neoplasias Ováricas , Síndrome de Turner , Femenino , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Gonadoblastoma/epidemiología , Gonadoblastoma/genética , Gonadoblastoma/patología , Síndrome de Turner/epidemiología , Síndrome de Turner/genética , Síndrome de Turner/diagnóstico , Prevalencia , Estudios de Seguimiento , Neoplasias Ováricas/patología , Cariotipo , MosaicismoRESUMEN
Objective: Childhood hyperthyroidism is mostly caused by Graves' disease, a rare autoimmune disease in children. Epidemiological data are scarce and the variability of within-region incidence is unknown. We aimed to provide the first description of temporal trends in pediatric hyperthyroidism in France and to explore spatial trends, with a view to identifying possible environmental triggers. Design and methods: We performed an observational population-based study on data collected from the National Health Data System, covering the 2008-2017 period and the whole of France. We identified patients with an indicator reflecting incident cases of treated hyperthyroidism, in children aged 6 months-17.9 years, localized at the scale of the département (equivalent to a county) of residence. We performed descriptive analyses of incidence rate by sex, age, and year, and used a spatiotemporal model for estimation at département level. Results: We identified 4734 incident cases: 3787 girls (80%) and 947 boys (20%). The crude incidence rate was 3.35 (95% CI: 3.26; 3.45) per 100 000 person-years over the study period. We estimated the increase in incidence between 2008 and 2017 at 30.1% (19.0%; 42.3%). Annual incidence rate increased linearly over the 10-year period in both girls and boys, rising similarly in all age groups and in all départements. The spatial model highlighted marked heterogeneity in the risk of childhood hyperthyroidism across France. Conclusion: The trend toward increasing incidence observed may reflect changes in genetic and environmental interactions, and the marked spatial heterogeneity may reflect localized ethnic or environmental factors worthy of further investigation.
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Enfermedades Autoinmunes , Enfermedad de Graves , Hipertiroidismo , Niño , Etnicidad , Femenino , Enfermedad de Graves/epidemiología , Humanos , Hipertiroidismo/epidemiología , Incidencia , MasculinoRESUMEN
Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
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Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Dexametasona/uso terapéutico , Europa (Continente)/epidemiología , Femenino , Humanos , Embarazo , Estudios ProspectivosRESUMEN
Hyperthyroidism caused by Graves' disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults - antithyroid drugs (ATD), radioactive iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. The European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.
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CONTEXT: The increase in the incidence of congenital hypothyroidism (CH) reported worldwide may partly be explained by an increase in the transient form of CH. OBJECTIVE: We aimed to estimate the proportion of transient CH (TCH) in France, and to identify associated neonatal and young child characteristics. METHODS: We used probabilistic record linkage to link children with eutopic gland born between 2006 and 2012 recorded in the national French CH registry and the French national health data system (SNDS). Of the 703 children recorded, 484 (68.8%) were linked. We retrospectively examined reimbursement for oral levothyroxine (LT4) between January 1, 2006, and December 31, 2017. Children who had discontinued treatment for 6 months or more before December 31, 2017, were classified as having TCH. We used a Cox model to examine the factors associated with TCH. RESULTS: Among the main study sample (nâ =â 471), 53.5% were female, 14.2% were preterm, and 13.8% had low birth weight. One-quarter (nâ =â 111, 24.3%) had mild CH (thyroid-stimulating hormone [TSH]â <â 50 mU/L, serum) at diagnosis and a median LT4 dose at treatment initiation of 30 µg/day. One-third (nâ =â 155, 32.9%) had TCH. Premature birth (adjusted hazard ratioâ =â 2.1 [1.0-4.2]), a TSHâ <â 50 mU/L at CH screening (7.4 [3.2-17.1]), LT4 dose received at 12 months of age (0.98 [0.97-0.99, Pâ =â 0.003]), congenital cardiac malformations (6.6 [1.5-29.0]), and year of birth (1.2 [1.1-1.4]) were all associated with TCH. CONCLUSION: One-third of the children had TCH, and it was associated with several characteristics at birth and postpartum. These data are useful for CH medical management and epidemiological surveillance.
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Hipotiroidismo Congénito , Enfermedades del Recién Nacido , Enfermedades Metabólicas , Niño , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/tratamiento farmacológico , Hipotiroidismo Congénito/epidemiología , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Masculino , Tamizaje Neonatal , Prevalencia , Estudios Retrospectivos , Tirotropina , Tiroxina/uso terapéuticoRESUMEN
Objectives: Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency. Study Design: We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500â nmol/l at LD-SST. Results: Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144â nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency. Conclusions: Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children.
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Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay. Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Graves' disease (GD) results from the passage of thyrotropin receptor antibodies (TRAbs) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking thyroid-stimulating hormone receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism, but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child's prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.
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Enfermedades Fetales/diagnóstico , Enfermedades de la Tiroides/diagnóstico , Glándula Tiroides/fisiopatología , Adulto , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Femenino , Enfermedades Fetales/inmunología , Enfermedades Fetales/fisiopatología , Humanos , Recién Nacido , Tamizaje Neonatal , Enfermedades de la Tiroides/inmunología , Enfermedades de la Tiroides/fisiopatología , Glándula Tiroides/inmunología , Tirotropina/inmunologíaRESUMEN
BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.
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Síndrome de Resistencia Androgénica , Enfermedades del Sistema Endocrino , Disgenesia Gonadal , Adulto , Preescolar , Estudios de Cohortes , Enfermedades del Sistema Endocrino/diagnóstico , Humanos , Recién Nacido , Masculino , Enfermedades Raras/diagnósticoRESUMEN
Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.
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Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/terapia , Adulto , Hormona Antimülleriana , Femenino , Hormona Folículo Estimulante , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Francia , Terapia de Reemplazo de Hormonas , HumanosRESUMEN
Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.
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Disgenesia Gonadal 46 XY , Disgenesia Gonadal , ARN Helicasas/genética , Disgenesia Gonadal 46 XY/genética , Humanos , Masculino , Fenotipo , Testículo/anomalíasRESUMEN
Congenital hypothyroidism (CH) is the leading cause of preventable mental retardation. It is mainly due to thyroid dysgenesis or dyshormonogenesis with normally located gland, and detected at birth in developed countries by systematic neonatal screening. The early treatment of patients with CH has successfully improved the prognosis and management of this disease. An increase in the incidence of congenital hypothyroidism with a normally located gland has been reported worldwide over the last three decades. The etiology of CH with a normally located gland remains elusive and about half of them demonstrate spontaneous resolution of CH within a few months (transient CH). They highlight the need to reevaluate thyroid function during follow-up.
TITLE: Dépistage de l'hypothyroïdie congénitale. ABSTRACT: L'hypothyroïdie congénitale est une maladie due à une sécrétion insuffisante d'hormones thyroïdiennes. Les causes sont multiples, mais les plus fréquentes sont dues à une anomalie de développement de la glande thyroïde ou à un trouble de l'hormonosynthèse thyroïdienne. Cette insuffisance thyroïdienne avait jadis des conséquences très graves sur le développement de l'enfant, dues essentiellement à un traitement bien trop tardif du déficit hormonal. Le dépistage néonatal systématique, mis en place depuis plus de 40 ans en France, permet actuellement une prise en charge dès le début de la deuxième semaine après la naissance. Il a transformé le pronostic de l'affection tant sur le plan de la croissance que sur celui du développement intellectuel et de l'insertion socio-professionnelle, qui sont normaux. Une augmentation de l'incidence de la maladie a été rapportée ces dernières années. Elle concerne essentiellement les formes avec glande thyroïde en place. Il est nécessaire de réévaluer la fonction thyroïdienne de ces patients car ces hypothyroïdies peuvent être transitoires.
Asunto(s)
Hipotiroidismo Congénito , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/epidemiología , Humanos , Incidencia , Recién Nacido , Tamizaje NeonatalRESUMEN
A major complication of feminizing genitoplasty in children is the loss of clitoral sensation with serious impact at adult life. We suggest a new method to evaluate the surgical results during childhood based on the bulbocavernosus or clitoro-perineal reflex (CPR). The afferent pathway of CPR implies the intact sensory receptors on the clitoral glans. Girls with congenital adrenal hyperplasia who were followed-up medically without surgery or who underwent feminizing genitoplasty with or without clitoroplasty were included (2002-2018). All clitoroplasties were standardized reduction clitoroplasty with preservation of neurovascular bundles associated with vaginoplasty and vestibuloplasty. Standardized examinations were prospectively performed including the CPR starting at one year postoperatively. The reflex was triggered by gentle touch of the glans by a cotton swab. Contraction of the perineal muscles was considered positive. Thirty-two children were operated at a median age of 8.6 months (5.8-12.1). Median follow-up (FU) was 3.9 years (1.3-6.4). Twenty-four patients had clitoroplasties: 17 were tested for CPR at one-year FU, and all had a positive test. Eight girls had genitoplasty without clitoral surgery, two of them were tested and were positive. Ten patients were managed without surgery, two of them were tested for the CPR and were positive. The reflex was always triggered easily and repeated at least twice during the FU. The clitoro-perineal reflex is a simple, non-invasive and reproducible test in early childhood and may serve as an early evaluation tool of clitoral innervation after feminizing genitoplasty. These results need to be confirmed at long term and completed at adult life.