ABSTRACT
CONTEXT: Pituitary stalk interruption syndrome (PSIS) is rare in the pediatric population. It combines ectopic posterior pituitary stalk interruption and anterior pituitary hypoplasia with hormonal deficiencies. The phenotype is highly heterogeneous and obesity/overweight seems to be underreported in the literature. OBJECTIVE: To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. METHODS: Sixty-nine children and young adults with PSIS in a Toulouse cohort from 1984 to 2019 were studied. We identified 25 obese or overweight patients (OB-OW group), and 44 were nonobese/overweight (NO group). Then the groups were compared. RESULTS: All cases were sporadic. The sex ratio was 1.6. The main reason for consultation in both groups was growth retardation (61% in OB-OW group, 77% in NO group). History of neonatal hypoglycemia was more common in the OB-OW than in the NO group (57% vs 14%, P = .0008), along with extrapituitary malformations (64% vs 20%, P < 0001). The incidence of caesarean section was higher in the OB-OW group (52%) than in the NO group (23%), although not significant (P = .07). CONCLUSION: Patients with PSIS who are obese/overweight display interesting phenotypic differences that suggest hypothalamic defects. Studies are needed that include additional information on hormonal levels, particularly regarding oxytocin and ghrelin.
Subject(s)
Pituitary Diseases , Pituitary Gland , Child , Female , Humans , Pregnancy , Cesarean Section , Obesity/complications , Obesity/epidemiology , Overweight/complications , Overweight/epidemiology , Pituitary Diseases/complications , Pituitary Diseases/epidemiology , Pituitary Diseases/genetics , Pituitary Gland/abnormalities , Young AdultABSTRACT
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.
Subject(s)
Endocrinology , Nuclear Medicine , Thyroid Neoplasms , Thyroid Nodule , Humans , Child , Adolescent , Thyroid Nodule/diagnosis , Thyroid Nodule/therapy , Thyroid Nodule/pathology , Radionuclide Imaging , Consensus , Thyroid Neoplasms/pathologyABSTRACT
Context: Congenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis. Objective: We explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype. Patients Design and Setting: Using the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity. Results: Among the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them. Conclusion: The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.
Subject(s)
Congenital Hypothyroidism/genetics , Autoantigens/genetics , Dual Oxidases/genetics , Female , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Infant , Infant, Newborn , Iodide Peroxidase/genetics , Iron-Binding Proteins/genetics , Male , Receptors, Thyrotropin/genetics , Symporters/geneticsABSTRACT
Inborn Errors of Metabolism (IEM) are rare and heterogenous disorders. For most IEMs, clinical signs are non-specific or belated. Late diagnosis is frequent, leading to death or severe sequelae. Some IEM induce intermediate metabolites circulating in the blood. They may be detected by tandem mass spectrometry. This method allows the simultaneous detection of many IEM in different metabolic pathways. In France, newborn screening (NBS) program for IEM, limited to phenylketonuria for decades, has been recently extended to medium chain acyl-CoA dehydrogenase deficiency. Rationale, methodology and organization of this new NBS program are described. Seven other IEM (maple syrup urine disease, homocystinuria, tyrosinemia type I, glutaric aciduria type I, isovaleric acidemia, long chain hydroxy-acyl-CoA dehydrogenase deficiency, carnitine uptake disorder) should be screened in the next program extension. Efforts are needed to fully understand the predictive value of each abnormal testing at birth, decrease the false positive rate, and develop the adequate management strategies.
TITLE: Les nouvelles maladies héréditaires du métabolisme du programme français de dépistage néonatal. ABSTRACT: Les maladies héréditaires du métabolisme (MHM) sont un groupe de maladies rares et cliniquement hétérogènes. Le retard diagnostique est fréquent, conduisant souvent au décès du patient ou à de graves séquelles. Certaines MHM entraînent l'accumulation de métabolites intermédiaires circulant dans le sang, qui sont détectables par une méthode commune utilisant la spectrométrie de masse en tandem. Cette méthode permet la reconnaissance simultanée de plusieurs de ces maladies affectant différentes voies métaboliques. En France, le programme de dépistage néonatal (DNN) des MHM, longtemps limité à la phénylcétonurie, a récemment été étendu au déficit en déshydrogénase des acyl-CoA à chaîne moyenne (MCADD). Le rationnel, la méthode et l'organisation de ce nouveau DNN sont décrits dans cet article. Sept nouvelles MHM (leucinose, homocystinurie, tyrosinémie de type I, acidurie glutarique de type I, acidurie isovalérique, déficit en déshydrogénase des hydroxy-acyl-CoA à chaîne longue, déficit du transporteur de la carnitine) devraient être dépistées, grâce à une prochaine extension du programme de DNN. Des efforts sont nécessaires pour mieux comprendre et prévoir la signification de chaque test anormal à la naissance, diminuer les taux de faux positifs, et développer les stratégies de prise en charge adéquates.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Lipid Metabolism, Inborn Errors , Metabolism, Inborn Errors , Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Congenital Bone Marrow Failure Syndromes , Humans , Infant, Newborn , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/epidemiology , Mitochondrial Diseases , Muscular Diseases , Neonatal ScreeningABSTRACT
CONTEXT: Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN). OBJECTIVE: To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986. DESIGN AND SETTING: Cohort study and nested case-control study. PARTICIPANTS: Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years). MAIN OUTCOME MEASURES: Occurrence of SN. RESULTS: In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study. CONCLUSION: This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.
Subject(s)
Cancer Survivors/statistics & numerical data , Human Growth Hormone/therapeutic use , Neoplasms, Second Primary/epidemiology , Adolescent , Adult , Aged , Brain Neoplasms/chemically induced , Brain Neoplasms/epidemiology , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Cranial Irradiation/adverse effects , Female , Follow-Up Studies , France/epidemiology , Hormone Replacement Therapy/adverse effects , Hormone Replacement Therapy/statistics & numerical data , Humans , Infant , Infant, Newborn , Male , Meningeal Neoplasms/chemically induced , Meningeal Neoplasms/epidemiology , Meningioma/chemically induced , Meningioma/epidemiology , Middle Aged , Neoplasms, Second Primary/chemically induced , Retrospective Studies , Young AdultABSTRACT
Inactivating germline pathogenic variants of the DICER1 gene are responsible for a spectrum of rare diseases, which expanded a lot in recent years. The constitution of an U.S. registry with these patients and their families as well as the registration of patients in European databases of rare tumors helped to better identify diseases encountered in this syndrome but also to study its pathophysiology (major role in miRNA maturation and recently discovered functions, e.g. in genome integrity maintenance). Most encountered disorders are pediatric malignancies, mainly the pulmonary pneumoblastoma and Sertoli-Leydig tumours. However, benign pathologies such as thyroid goiters, cystic nephromas or pulmonary cystic lesions are also frequently reported. Homogeneous guidelines regimens written by the European groups working on very rare pediatric tumors are proposed but it is important to underscore that they rely on rare scientific data; therefore overall consensus remains precarious. The genetic counseling to families is still difficult due to the large observed spectrum of tumors and the incomplete penetrance. In this article, the authors update current knowledge on the DICER1 syndrome.
Subject(s)
DEAD-box RNA Helicases/genetics , Neoplasms/genetics , Rare Diseases/genetics , Ribonuclease III/genetics , DEAD-box RNA Helicases/metabolism , Female , Genetic Counseling , Humans , Kidney Neoplasms/diagnosis , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Neoplasms/diagnosis , Neoplasms/metabolism , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Rare Diseases/diagnosis , Rare Diseases/metabolism , Ribonuclease III/metabolism , SyndromeABSTRACT
BACKGROUND: DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low-to-moderate penetrance of tumour development, which is sex- and age-dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females. PATIENTS AND METHODS: We report a series of eight families referred for childhood-onset of MNG or DICER1-related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools. RESULTS: Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives. CONCLUSIONS: Multinodular goitre is uncommon in children. Childhood-onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.
Subject(s)
DEAD-box RNA Helicases/genetics , Goiter, Nodular/metabolism , Goiter, Nodular/pathology , Ribonuclease III/genetics , Adolescent , Child , Female , Genetic Predisposition to Disease , Goiter, Nodular/genetics , High-Throughput Nucleotide Sequencing , Humans , Male , Mutation/genetics , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Neoplastic Syndromes, Hereditary/pathology , PedigreeABSTRACT
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.
Subject(s)
Membrane Transport Proteins/administration & dosage , Mental Retardation, X-Linked/drug therapy , Muscle Hypotonia/drug therapy , Muscular Atrophy/drug therapy , Triiodothyronine/analogs & derivatives , Adolescent , Child , Child, Preschool , Europe , Follow-Up Studies , Guidelines as Topic , Humans , Infant , Male , Membrane Transport Proteins/pharmacology , Mental Retardation, X-Linked/physiopathology , Muscle Hypotonia/physiopathology , Muscular Atrophy/physiopathology , Patient Safety , South Africa , Triiodothyronine/administration & dosage , Triiodothyronine/pharmacology , Young AdultABSTRACT
Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.
Subject(s)
Chromosome Disorders/genetics , Chromosomes, Human, Pair 14/genetics , Silver-Russell Syndrome/genetics , Adolescent , Adult , Calcium-Binding Proteins , Child , Child, Preschool , Chromosome Deletion , Chromosome Disorders/diagnosis , DNA Methylation/genetics , Diagnosis, Differential , Female , Genomic Imprinting/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Membrane Proteins/genetics , Phenotype , Puberty, Precocious/genetics , RNA, Long Noncoding/genetics , Retrospective Studies , Silver-Russell Syndrome/diagnosis , Syndrome , Uniparental Disomy , Young AdultABSTRACT
We describe severe thyrotoxicosis in young members of a family with nonautoimmune hyperthyroidism caused by a C672W germline mutation in exon 10 of TSHR gene. In this family, lack of genotype-phenotype correlation and anticipation across generations could be linked to an increased iodine intake as recently observed in France.
ABSTRACT
Context: LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is â¼1.4% in the 417 probands tested.