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BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant. METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network. RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results. CONCLUSION: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.
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DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Deficiência Intelectual , Humanos , Masculino , Feminino , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , França/epidemiologia , Criança , DNA (Citosina-5-)-Metiltransferases/genética , Pré-Escolar , Adolescente , Mutação em Linhagem Germinativa/genética , Adulto , Fenótipo , Adulto Jovem , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , LactenteRESUMO
Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.
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Densidade Óssea , Colestanotriol 26-Mono-Oxigenase/deficiência , Raquitismo Hipofosfatêmico Familiar/complicações , Adolescente , Adulto , Consanguinidade , Família 2 do Citocromo P450 , Humanos , Vitamina D/sangueRESUMO
Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identification of genetic predictors by genome exome sequencing and their influence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could influence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most significant associations in 81 other cases. The analysis of exome sequencing identified one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identified five gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMT and GLI3 with NTD risk in the 81 cases. We found a significant hemimethylation of CFAP46 that may influence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identified new candidate genes and rare variants that highlight an interacting influence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.
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Biomarcadores/metabolismo , Carbono/metabolismo , Exoma , Proteínas Hedgehog/genética , Defeitos do Tubo Neural/genética , Vitamina B 12/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Masculino , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/patologia , Transdução de Sinais , Sequenciamento do Exoma , Adulto JovemRESUMO
AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5â¯years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2â¯mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500⯵mol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500⯵mol/L.
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Alcaptonúria/diagnóstico por imagem , Alcaptonúria/tratamento farmacológico , Cicloexanonas/administração & dosagem , Nitrobenzoatos/administração & dosagem , Adulto , Pré-Escolar , Dieta , Relação Dose-Resposta a Droga , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Tirosina/sangue , Adulto JovemRESUMO
Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.
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Paralisia Cerebral/tratamento farmacológico , Osteoporose/tratamento farmacológico , Síndrome de Rett/tratamento farmacológico , Ácido Zoledrônico/uso terapêutico , Adolescente , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiopatologia , Criança , Fraturas Ósseas/tratamento farmacológico , Humanos , Imidazóis/uso terapêutico , Fatores de Tempo , Ácido Zoledrônico/administração & dosagemRESUMO
The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse experimental designs. However, no study to date has summarized their findings. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to September 2022 to identify monogenic non-syndromic obesity gene screening studies. Of 1051 identified references, 31 were eligible after title and abstract screening and 28 after full-text reading and risk of bias and quality assessment. Most studies (82%) used NGS methods. The number of genes screened varied from 2 to 12 genes from the leptin-melanocortin pathway. While all the included studies used in silico tools to assess the functional status of mutations, only 2 performed in vitro tests. The prevalence of carriers of pathogenic/likely pathogenic monogenic mutations is 13.24% on average (heterozygous: 12.31%; homozygous/heterozygous composite: 0.93%). As no study reported the penetrance of pathogenic mutations on obesity, we estimated that homozygous carriers exhibited a complete penetrance (100%) and heterozygous carriers a variable penetrance (3-100%). The review provides an exhaustive description of sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in monogenic non-syndromic obesity genes.
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Leptina , Melanocortinas , Mutação , Obesidade , Penetrância , Humanos , Obesidade/genética , Leptina/genética , Melanocortinas/genética , Sequenciamento de Nucleotídeos em Larga Escala , PrevalênciaRESUMO
Patients with monogenic obesity display numerous medical features on top of hyperphagic obesity, but no study to date has provided an exhaustive description of their semiology. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to January 2022 to identify studies that described symptoms of patients carrying pathogenic mutations in at least one of eight monogenic obesity genes (ADCY3, LEP, LEPR, MC3R, MC4R, MRAP2, PCSK1, and POMC). Of 5207 identified references, 269 were deemed eligible after title and abstract screening, full-text reading, and risk of bias and quality assessment. Data extraction included mutation spectrum and mode of inheritance, clinical presentation (e.g., anthropometry, energy intake and eating behaviors, digestive function, puberty and fertility, cognitive features, infectious diseases, morphological characteristics, chronic respiratory disease, and cardiovascular disease), biological characteristics (metabolic profile, endocrinology, hematology), radiological features, and treatments. The review provides an exhaustive description of mandatory, non-mandatory, and unique symptoms in heterozygous and homozygous carriers of mutation in eight monogenic obesity genes. This information is critical to help clinicians to orient genetic testing in subsets of patients with suspected monogenic obesity and provide actionable treatments (e.g., recombinant leptin and MC4R agonist).
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OBJECTIVE: To evaluate the impact of antenatal corticosteroid therapy (ACS) on birth outcomes in term infants exposed during pregnancy. STUDY DESIGN: Exposed newborns were compared with non-exposed controls in a 1 to 2 design. Multivariate analysis was used to assess the effect of ACS exposure on neonatal outcomes. RESULT: 408 newborns were included (136 exposed to ACS, 272 non-exposed). Mean ± SD head circumference (HC) was 33.7 ± 1.4 vs 34.3 ± 1.6 cm, p = 0.001 in exposed vs controls; birth weight was 3.1 ± 0.4 vs 3.3 ± 0.4 kg, p = 0.0001; and birth height was 47.9 ± 2.1 vs. 49.1 ± 2.0 cm, p < 0.0001. Hypocalcemia (4.4 vs 0.7%, p = 0.019) and feeding difficulties (5.1 vs 1.5%, p = 0.047) were significantly more common in exposed newborns. Multivariate analysis for HC showed a significant independent association with ACS exposure (ß = -0.5, p = 0.009). CONCLUSION: Term newborns exposed to ACS have lower birth HC and higher risk of neonatal complications. CLINICAL TRIAL REGISTRATION: NCT05640596.
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Trabalho de Parto Prematuro , Nascimento Prematuro , Lactente , Recém-Nascido , Humanos , Feminino , Gravidez , Corticosteroides/efeitos adversos , Peso ao Nascer , Análise Multivariada , Estudos Retrospectivos , Idade GestacionalRESUMO
BACKGROUNDS: Childhood obesity is a real public health concern because of its association with a higher risk of adulthood obesity and comorbidities (metabolic, cardiovascular, etc.). The factors associated with the effectiveness of care are poorly described. The objective of this study was to identify factors associated with body mass index (BMI) variation in the management of childhood obesity. MATERIAL AND METHODS: Children followed up for obesity in the Pediatric Endocrinology Department of the University Children Hospital of Nancy were included. Data were retrospectively collected in medical files. The characteristics of patients with a decrease in BMI (in standard deviation score, SDS) were compared with patients with an increased BMI (SDS)after 1 year of follow-up through univariate analysis. RESULTS: Overall, 141 patients were included, and for 107 patients (55 girls and 52 boys) there were 1-year follow-up data. The mean BMI variation after 1 year of follow-up was-0.068 SD and for 63 patients (58.9%) there was a decrease in BMI SDS. Female patients (66% vs. 41%, p=0.012), hypercholesterolemia (33% vs. 4%, p=0.049), and type 1 diabetes (14% vs. 2%, p=0.019) were more frequent in patients with an unfavorable evolution of BMI SDS at 1 year. A family history of bariatric surgery (36% vs. 11%, p=0.042) or eating behavior disorders (76% vs. 24% of patients; p<0.001) or diabetes (1st or 2nd degree;81% vs. 60%, p=0.044) were also more frequent in children with an unfavorable evolution of BMI SDS at 1 year. CONCLUSION: Several negative factors in the evolution of BMI were identified such as female sex, hypercholesterolemia, family history of bariatric surgery, or eating behavior. Early identification of these patients at risk of failure of obesity management is important to control BMI during childhood.
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Hipercolesterolemia , Obesidade Infantil , Masculino , Humanos , Criança , Feminino , Adulto , Obesidade Infantil/epidemiologia , Obesidade Infantil/terapia , Estudos de Coortes , Estudos Retrospectivos , Índice de Massa CorporalRESUMO
OBJECTIVES: More than one third of children with congenital hypothyroidism (CH) and thyroid gland in situ (or eutopic gland) have transient hypothyroidism. It remains difficult to determine early on whether hypothyroidism will be transient which may cause overtreatment and its complications in these children. Our primary aim was to determine prognostic factors for transient hypothyroidism in children with congenital hypothyroidism and eutopic gland or thyroid hemiagenesis. METHODS: We retrospectively reviewed medical records of 111 children, born between 1996 and 2017, diagnosed with congenital hypothyroidism and eutopic gland or hemiagenesis and treated at the Nancy Regional and University Hospital. RESULTS: Fifty four infants (48.6%) had permanent congenital hypothyroidism (PCH) and 57 (51.4%) transient congenital hypothyroidism (TCH). Prognostic factors for TCH included prematurity, twin pregnancy, low birth weight and Apgar score <7, while low FT3 at diagnosis, maternal levothyroxine treatment, a family history of thyroid dysfunction and TSH ≥10 mUI/L while receiving treatment were associated with PCH. Knee epiphyses on X-ray at diagnosis were absent only in children with PCH. The median levothyroxine dose during follow-up was significantly lower in the TCH group compared to the PCH group. A levothyroxine dose of ≤3.95, ≤2.56, ≤2.19 and ≤2.12 µg/kg/day at 6 months, 1, 2 and 3 years of follow-up, respectively, had the best sensitivity-to-specificity ratio for predicting TCH. CONCLUSIONS: Even though it remains difficult to predict the course of hypothyroidism at diagnosis, we were able to identify several prognostic factors for TCH including perinatal problems and lower levothyroxine requirements that can guide the physician on the evolution of hypothyroidism. Clinical Trial Registration Number: NCT04712760.
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Hipotireoidismo Congênito , Disgenesia da Tireoide , Recém-Nascido , Lactente , Humanos , Criança , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Tiroxina/uso terapêutico , Estudos Retrospectivos , Prognóstico , Tireotropina , Triagem NeonatalRESUMO
BACKGROUND: Ambulatory exams were preferred in children during the COVID-19 pandemic. Polysomnography (PSG), the gold standard for obstructive sleep apnea (OSA) diagnosis, requires several leads and sensors to be attached to the child's body. Children are more comfortable with respiratory polygraphic (RP) recording, which needs fewer sensors. OBJECTIVE: To compare respiratory parameters obtained by home RP with those obtained by home PSG with the device installed at the child's home by a trained sleep nurse from a national health care provider. METHODS: Data from home PSGs performed in children aged 2-19 years were retrospectively included. The obstructive apnea-hypopnea index (OAHI) was computed in PSG and then in RP after removing the sleep signals. The two indexes were compared using non-parametric paired Wilcoxon rank test, Bland-Altman analysis and sensitivity-specificity analysis. RESULTS: 44 PSGs of 44 children were included with only 34 (77%) PSGs interpretable. Median (min-max) OAHI was significantly underestimated in RP than in PSG (2.2 (0-25) vs 4.0 (0.4-28), p < 0.0001), confirmed also by the Bland-Altman diagram, the magnitude of the difference being mean ± standard deviation -1.7 ± 1.7. The sensitivity and specificity of OAHI in RP to identify an OAHI ≥2/h in PSG was 0.91 for both. CONCLUSION: Unattended ambulatory RP performed at child's house and installed under carefully controlled conditions is a useful exam for diagnosing OSA in children with or without comorbidities. However, RP must be installed in a supervised environment and interpreted with caution as it tends to underestimate OSA severity.
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COVID-19 , Apneia Obstrutiva do Sono , Humanos , Criança , Polissonografia , Pandemias , Estudos Retrospectivos , COVID-19/diagnóstico , Apneia Obstrutiva do Sono/diagnóstico , Sono , Teste para COVID-19RESUMO
OBJECTIVE: Heterozygous variations in microtubule-associated serine/threonine kinase 1 gene (MAST1) were recently described in the mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM, MIM 618273), revealing the importance of the MAST genes family in global brain development. To date, patients with MAST1 gene mutations were mostly young children with central nervous system involvement, impaired motor function, speech delay, and brain magnetic resonance imaging (MRI) abnormalities. Here, we report the clinical presentation of an adult patient with a rare and de novo MAST1 mutation with central hypogonadism that could extend this phenotype. METHODS: A panel of 333 genes involved in epilepsy or cortical development was sequenced in the described patient. Routine biochemical analyses were performed, and hormonal status was investigated. RESULT: We report a 22-year-old man with a de novo, heterozygous missense variant in MAST1 (Chr19(GRCh37):g.12975903G > A, NP_055790.1:p.Gly517Ser). He presented with an epileptic encephalopathy associated with cerebral malformations, short stature, hypogonadotropic hypogonadism, and secondary osteopenia. CONCLUSION: This is the first patient with MAST1 gene mutation described with central hypogonadism, which may be associated with the phenotype of MCCCHCM syndrome.
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Hipogonadismo , Leucoencefalopatias , Malformações do Sistema Nervoso , Criança , Masculino , Humanos , Pré-Escolar , Adulto Jovem , Adulto , Malformações do Sistema Nervoso/genética , Leucoencefalopatias/genética , Mutação , Microtúbulos , Hipogonadismo/genéticaRESUMO
BACKGROUND: Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported. METHODS: This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria. RESULTS: Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size. CONCLUSIONS: This study's high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.
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Variações do Número de Cópias de DNA , Estudos Retrospectivos , Transtorno do Espectro Autista/genética , Transtornos do Neurodesenvolvimento/genética , HumanosRESUMO
CONTEXT: Patients with type 1 diabetes (T1D) are more likely to develop other autoimmune diseases than the general population. OBJECTIVES: To describe additional autoimmunity in a cohort of children and adolescents with T1D, as well as to identify factors associated with the presence of additional autoantibodies (AABs) and of additional autoimmune diseases (AADs). SETTING: This was a single-center retrospective cohort study of 179 children and adolescents (median age: 9.1 years) diagnosed with T1D between 2014 and 2020 in a specialized center in France. Patients were screened for autoimmune thyroiditis and celiac disease at T1D diagnosis and once every 1-2 years during follow-up. Other AADs and their specific autoantibodies were screened for only if clinical or laboratory signs were present. RESULTS: At T1D diagnosis, 15.6% of participants presented with at least one type of AAB including antibodies specific to Hashimoto's disease (TPOAb and/or TGAb) and/or to celiac disease (tTGAb and/or EMAb). Only 2.8% of participants presented with an AAD as early as T1D diagnosis. The median follow-up was 37 months. The cumulative incidence of AABs and AADs at 2 years of follow-up was, respectively, 3.9% and 5.4%, and it doubled at 3 years of follow-up. Only one patient, also affected by Down syndrome, was diagnosed with 2 AADs. Hashimoto's disease was the most frequently diagnosed AAD, followed by celiac disease, both at an asymptomatic stage. Vitiligo and Graves' disease were also diagnosed in this cohort but affected few patients. Children aged 6-12 years were more likely to present with an AAD at diabetes diagnosis (p = 0.043). CONCLUSION: The high prevalence and incidence of additional autoimmunity in children and adolescents with T1D justifies regular screening of AABs and AADs.
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Doenças Autoimunes , Doença Celíaca , Diabetes Mellitus Tipo 1 , Doença de Graves , Doença de Hashimoto , Adolescente , Autoanticorpos , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Doença de Graves/complicações , Doença de Hashimoto/complicações , Humanos , Estudos RetrospectivosRESUMO
Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily. Nineteen children were included in the EFFET trial. The primary efficacy outcome was improvement of Autism Diagnostic Observation Schedule (ADOS) score. The secondary outcomes were the improvement in ADOS sub scores communication, social interactions, Social Responsiveness Score (SRS) and treatment safety. The global ADOS score and social interaction and communication sub scores were significantly improved at week 12 compared to baseline in the folinic acid group (P = 0.003, P = 0.004 and P = 0.022, respectively), but not in the placebo group (P = 0.574, P = 0.780, P = 0.269, respectively). We observed a greater change of ADOS global score (-2.78 vs. -0.4 points) and (-1.78 vs. 0.20 points) in the folinic acid group, compared to the placebo group. No serious adverse events were observed. This pilot study showed significant efficacy of folinic acid with an oral formulation that is readily available. It opens a perspective of therapeutic intervention with folinic acid but needs to be confirmed by a multi-center trial on a larger number of children.
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Transtorno do Espectro Autista/tratamento farmacológico , Leucovorina/administração & dosagem , Administração Oral , Criança , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
OBJECTIVE: We report an exceptional case of non-islet cell tumor-induced hypoglycemia (NICTH) secondary to "Big"-IGF-2 oversecretion due to a giant phyllode tumor of the breast. CLINICAL PRESENTATION: A 49-year-old woman was admitted in emergency for brutal neurologic defect revealing severe hypoglycemia. Several similar episodes were observed throughout hospitalization, requiring continue perfusion of hypertonic glucose solution. Beside these metabolic disorders, we observed a giant and hard tumor of the left breast (about 30cm in diameter). INTERPRETATION: Supplementary blood analysis revealed serum levels of C-peptide and insulin suppressed during hypoglycemia, excluding the possibility of either endogenous or exogenous hyperinsulinism. Low plasma levels of GH and IGF-1 were found, suggesting a negative feedback loop on somatotroph axis function. Therefore, the hypothesis of an insulinomimetic compound released by tumor cells was evoked because of abnormal presence of high-weight and immature form of IGF-2 (called "Big"-IGF-2) in the serum identified by western immunoblot analysis. A left mastectomy was performed and completely restored glucose homeostasis and confirmed the paraneoplastic origin of hypoglycemia because of markedly elevated expression of IGF-2 mRNA (qPCR) within the tumor cells. Finally, the anatomopathology analysis diagnosed a mesenchymatous tumor, namely a high-grade phyllode sarcoma of the breast. CONCLUSION: Although NICTH due to "Big"-IGF-2 overproduction is a rare phenomenon, mainly observed in case of mesenchymatous tumor, it should be considered in presence of severe hypoglycemia with voluminous tumor and without hyperinsulinism.