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Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.
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Approximately 10,000 children in France with growth hormone deficiency (GHD) are being administered daily recombinant human growth hormone (rhGH). Although this treatment has long proved efficient for restoring children's growth and metabolism, daily injections of rhGH have a few limitations, such as difficulties in terms of adherence to treatment, which may compromise growth during childhood but also metabolism in adulthood. In addition to the disease burden and besides the adherence hurdles, the obligations related to daily injection have a negative impact on the quality of life of patients and their families. The hypothesis that injections administered at intervals of 1 week, or even 1 month, could improve compliance, reduce treatment discontinuations, and optimize quality of life and therapeutic effectiveness has led to the emergence of new long-acting growth hormone (LAGH). Recent access to LAGHs (somatrogon MA) on the European and French market will likely be followed by a high demand from the families concerned and may raise questions on their effectiveness, safety, and practical use. Numerous practical and practice-related points are needed to guide prescribing physicians while many concerns are still left unresolved (treatment effectiveness or ineffectiveness endpoints, long-term effectiveness, etc.). These issues can only be addressed in the future by compiling registries and conducting long-term real-world studies.
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OBJECTIVE: To evaluate the impact of prolonged hybrid closed loop (HCL) use in children with type 1 diabetes (T1D) on glucose control and BMI throughout pubertal progression. RESEARCH DESIGN AND METHODS: We used a prospective multicenter extension study following the Free-Life Kid AP (FLKAP) HCL trial. The 9-month previously reported FLKAP trial included 119 prepubertal children (aged 6-12 years). During the extension study, participants could continue to use HCL for 30 months (M9 to M39). HbA1c values were collected every 3 months up to M39, while continuous glucose monitoring metrics, BMI Z scores, and Tanner stages were collected up to M24. Noninferiority tests were performed to assess parameter sustainability over time. RESULTS: One hundred seventeen children completed the extension study, with mean age 10.1 years (min-max 6.8-14.0) at the beginning. Improvement of HbA1c obtained in the FLKAP trial was significantly sustained during extension (median [interquartile range], M9: 7.0% [6.8-7.4], and M39: 7.0% [6.6-7.4], P < 0.0001 for noninferiority test) and did not differ between children who entered puberty at M24 (Tanner ≥ stage 2; 54% of the patients) and patients who remained prepubertal. BMI Z score also remained stable (M9: 0.41 [-0.29 to 1.13] and M24: 0.48 [-0.11 to 1.13], P < 0.0001, for noninferiority test). No severe hypoglycemia and one ketoacidosis episode not related to the HCL system occurred. CONCLUSIONS: Prolonged use of HCL can safely and effectively mitigate impairment of glucose control usually associated with pubertal progression without impact on BMI in children with T1D.
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PURPOSE: The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. METHODS: An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/ß1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. RESULTS: The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. CONCLUSION: Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.
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Displasia Fibrosa Poliostótica , Pubertad Precoz , Femenino , Humanos , Displasia Fibrosa Poliostótica/diagnóstico , Mutación con Ganancia de Función , Células HEK293 , Ovario , Pubertad Precoz/etiologíaRESUMEN
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
CONTEXT: The increase in bone mineral content (BMC) and density (BMD) measured by dual-energy x-ray absorptiometry (DXA) in obese children may not sustain the mechanical load associated with weight, and the factors influencing bone mineralization are not well known. OBJECTIVE: We described bone mineralization in boys with overweight/obesity and leanness in relation to body composition. METHODS: Cross-sectional study in the Pediatric Endocrinology Unit of Angers University Hospital with 249 overweight/obese boys aged 8-18 who underwent DXA and insulin, testosterone, and IGF-1 measurements. Bone mineralization was compared with data from 301 lean boys of similar age and height from NHANES 2011-2015, using the same DXA model. Path analyses were performed to evaluate factors associated with total body less head (TBLH) BMC. RESULTS: The mean age- and height-adjusted difference in TBLH BMC between obese and lean boys was 241 ± 20 g/cm2. Each 1 kg/m2 increase in BMI was associated with +39 ± 6 g of TBLH BMC in lean subjects vs + 25 ± 3 g in obese subjects (P < .05). Each 1 kg/m2 increase in lean BMI (LBMI) was associated with +78 ± 5 g of TBLH BMC in lean and obese boys, and each 1 kg/m2 increase in fat mass index (FMI) was associated with a decrease of 9 ± 3 g of TBLH BMC. The TBLH BMC was directly positively influenced by LBMI and indirectly and positively influenced by IGF-1, testosterone, and insulin (mediated through height and LBMI). FMI indirectly influenced TBLH BMC, both positively through LBMI and negatively through its negative impact on IGF-1 and testosterone. CONCLUSION: The increase in bone mineralization in obese children does not adapt to the increase in body mass.
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Composición Corporal , Densidad Ósea , Humanos , Masculino , Estudios Transversales , Niño , Adolescente , Densidad Ósea/fisiología , Composición Corporal/fisiología , Absorciometría de Fotón , Calcificación Fisiológica/fisiología , Obesidad Infantil/fisiopatología , Obesidad Infantil/metabolismo , Índice de Masa Corporal , Peso Corporal/fisiología , Soporte de Peso/fisiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisisRESUMEN
OBJECTIVES: The aim of this study is to analyze height after cessation of growth (final height [FH]) and its evolution over the last decades in X-linked hypophosphatemia (XLH) patients in France, as the data on natural history of FH in XLH are lacking. DESIGN: We performed a retrospective observational study in a large cohort of French XLH patients with available data on FH measurements. MATERIALS AND METHODS: We divided patients into 3 groups according to their birth year: group 1 born between 1950 and 1974, group 2 born between 1975 and 2000, and group 3 born between 2001 and 2006, respectively, and compared their FHs. RESULTS: A total of 398 patients were included. Mean FHs were the following: for group 1, -2.31 ± 1.11 standard deviation score (SDS) (n = 127), 156.3 ± 9.7â cm in men and 148.6 ± 6.5â cm in women; for group 2, -1.63 ± 1.13 SDS (n = 193), 161.6 ± 8.5â cm in men and 153.1 ± 7.2â cm in women; and for group 3, -1.34 ± 0.87 SDS (n = 78), 165.1 ± 5.5â cm in men and 154.7 ± 6â cm in women. We report a significant increase in mean FH SDS over 3 generations of patients, for both men and women (P < .001). Final height SDS in male (-2.08 ± 1.18) was lower than in female (-1.70 ± 1.12) (P = .002). CONCLUSION: The FH of XLH patients in France increased significantly over the last decades. Even though men's FHs improved more than women's, men with XLH remain shorter reflecting a more severe disease phenotype. While the results are promising, most patients with XLH remain short leaving room for improvement.
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Raquitismo Hipofosfatémico Familiar , Hipofosfatemia , Humanos , Masculino , Femenino , Adulto , Raquitismo Hipofosfatémico Familiar/genética , Estudios de Cohortes , Estatura , Estudios Retrospectivos , Endopeptidasa Neutra Reguladora de Fosfato PHEX , Hipofosfatemia/genéticaRESUMEN
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.
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Calcinosis , Fracturas Múltiples , Hipofosfatasia , Osteogénesis Imperfecta , Osteomalacia , Raquitismo , Niño , Humanos , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis Imperfecta/genética , Hipofosfatasia/tratamiento farmacológico , Hipofosfatasia/genética , Osteomalacia/genética , Osteomalacia/patología , Mutación , Fosfatasa Alcalina/genéticaRESUMEN
Acromegaly is a rare disease with prevalence of approximately 60 cases per million, slight female predominance and peak onset in adults in the fourth decade. Clinical diagnosis is often delayed by several years due to the slowly progressive onset of symptoms. There are multiple clinical criteria that define acromegaly: dysmorphic syndrome of insidious onset, symptoms related to the pituitary tumor (headaches, visual disorders), general signs (sweating, carpal tunnel syndrome, joint pain, etc.), complications of the disease (musculoskeletal, cardiovascular, pneumological, dental, metabolic comorbidities, thyroid nodules, colonic polyps, etc.) or sometimes clinical signs of associated prolactin hypersecretion (erectile dysfunction in men or cycle disorder in women) or concomitant mass-induced hypopituitarism (fatigue and other symptoms related to pituitary hormone deficiencies). Biological confirmation is based initially on elevated IGF-I and lack of GH suppression on oral glucose tolerance test or an elevated mean GH on repeated measurements. In confirmed cases, imaging by pituitary MRI identifies the causal tumor, to best determine management. In a minority of cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context. The first-line treatment is most often surgical removal of the somatotroph pituitary tumor, either immediately or after transient medical treatment. Medical treatments are most often proposed in patients not controlled by surgical removal. Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.
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Acromegalia , Hormona de Crecimiento Humana , Neoplasias Hipofisarias , Masculino , Adulto , Humanos , Femenino , Acromegalia/diagnóstico , Acromegalia/etiología , Acromegalia/terapia , Hormona de Crecimiento Humana/uso terapéutico , Hormona de Crecimiento Humana/metabolismo , Neoplasias Hipofisarias/cirugía , Prueba de Tolerancia a la Glucosa , Protocolos ClínicosRESUMEN
Childhood obesity is associated with many comorbidities. Bariatric surgery is known to be efficient for reducing weight in adolescents. Objectives: The primary outcome was to identify somatic or psychosocial factors associated with success at 24 months after a laparoscopic adjustable gastric banding (LAGB) procedure in our cohort of adolescents with severe obesity. Secondary endpoints were to describe weight loss outcomes, comorbidity resolution, and complications. Methods: We have retrospectively reviewed medical records of patients who had LAGB placed between 2007 and 2017. Factors associated with success at 24 months after LAGB were researched, with success being defined as positive percentage of excess weight loss (%EWL) at 24 months. Results: Forty-two adolescents underwent a LAGB procedure, the mean %EWL was 34.1% at 24 months, with improvement in most comorbidities and without major complications. Having lost weight before surgery was associated with success, whereas a high body mass index at surgery was associated with a higher risk of failure. No other factor was found to be associated with success. Conclusion: Comorbidities mostly improved 24 months after LAGB and no major complication occurred. Having lost weight before surgery was associated with a successful surgery, whereas a high body mass index at surgery increases the risk of failure.
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INTRODUCTION: Growth hormone (GH) therapy improves height outcomes in short children born small for gestational age (SGA); however, real-world data on long-term GH exposure are few. METHODS: We report results from an observational study (NCT01578135) including children born SGA, treated with GH at 126 sites in France, and followed up for >5 years until achieving final adult height (FAH) or until study termination. Primary endpoints were the proportion of patients with normal (>-2) height standard deviation score (SDS) at the last visit and with normal FAH SDS. Post hoc analyses were performed by multivariate logistic regression analysis with stepwise elimination to identify factors associated with GH dose modulation and normal height SDS achievement. RESULTS: Of 1,408 registered patients, a representative sample (n = 291) was selected for long-term follow-up. At the last visit, 193/291 (66.3%) children achieved normal height SDS and 72/291 (24.7%) reached FAH. FAH SDS was >-2 for chronological age in 48 (66.7%) children and >-2 for adult age in 40 (55.6%) children. In the post hoc analyses, height SDS at the last visit was a significant determinant of whether GH dose had been modulated. Factors significantly associated with reaching normal height SDS were baseline height SDS (taller, better), age at treatment start (younger, better), treatment duration excluding discontinuation periods (longer, better), and absence of a chronic disease. Most (70%) adverse events were non-serious, with 39% considered possibly/probably related to GH treatment. CONCLUSIONS: GH therapy was fairly effective in most short children born SGA. No new safety concerns were identified.
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Estatura , Hormona de Crecimiento Humana , Adulto , Niño , Humanos , Recién Nacido , Edad Gestacional , Hormona de Crecimiento Humana/uso terapéutico , Recién Nacido Pequeño para la Edad GestacionalRESUMEN
Background: It is unclear whether hybrid closed-loop (HCL) therapy attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump (SAP) therapy in children with type 1 diabetes in free-living conditions. Methods: This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL with evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an E/N HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases were analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70-180 mg/dL) according to the number of missed boluses per day. Findings: TIR was 54% ± 10% with SAP, 63% ± 7% with E/N HCL, and steadily 67% ± 7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% confidence intervals [CI] 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6-28), respectively, in the 24/7 HCL phase (P < 0.05 for all comparisons vs. SAP). Interpretation: HCL persistently improves glycemic control compared with SAP, even in case of meal bolus omission. ClinicalTrials.gov (NCT03739099).
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Diabetes Mellitus Tipo 1 , Humanos , Niño , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Glucemia/metabolismo , Sistemas de Infusión de Insulina , Insulina/uso terapéutico , Automonitorización de la Glucosa SanguíneaRESUMEN
Objective: The objective of this study was to describe in a real-life setting the treatment burden and adherence and quality of life (QOL) of children treated with daily injections of growth hormone and their relationship with treatment duration. Design: This non-interventional, multicenter, cross-sectional French study involved children aged 3-17 years treated with daily growth hormone injections. Methods: Based on a recent validated dyad questionnaire, the mean overall life interference total score (100 = most interference) was described, with treatment adherence and QOL, using the Quality of Life of Short Stature Youth questionnaire (100 = best). All analyses were performed according to treatment duration prior to inclusion. Results: Among the 275/277 analyzed children, 166 (60.4%) had only growth hormone deficiency (GHD). In the GHD group, the mean age was 11.7 ± 3.2 years; median treatment duration was 3.3 years (interquartile range 1.8-6.4). The mean overall life interference total score was 27.7 ± 20.7 (95% CI (24.2; 31.2)), with non-significant correlation with treatment duration (P = 0.1925). Treatment adherence was good (95.0% of children reported receiving >80% of planned injections over the last month); it slightly decreased with treatment duration (P = 0.0364). Children's overall QOL was good (81.5 ± 16.6 and 77.6 ± 18.7 according to children and parents, respectively), but subscores of the coping and treatment impact domains were <50. Similar results were observed in all patients independently of the condition requiring treatment. Conclusions: This real-life French cohort confirms the treatment burden of daily growth hormone injections, as previously reported in an interventional study.
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Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing variants or mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here, we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia and bone marrow failure. Exome sequencing revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21dup; p.Asp8ArgfsTer3 and c.842 + 15 T > C inherited from their unaffected mother and father, respectively. The c.21dup variant led to a premature stop codon generated in exon 1 of the ZNT7 coding sequence. RNA-seq analysis demonstrated that the c.842 + 15 T > C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Moreover, the expression of ZNT7 protein was remarkably reduced by 80-96% in the affected brothers compared to the control cells. These findings strongly suggest that biallelic variants in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia and syndromic bone marrow failure.
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Proteínas de Transporte de Catión , Hipogonadismo , Masculino , Humanos , Ratones , Animales , Hermanos , Codón sin Sentido , Trastornos de Fallo de la Médula Ósea , Hipogonadismo/genética , Zinc/metabolismo , Trastornos del Crecimiento , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismoRESUMEN
Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13-39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants' families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS.
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Síndrome de Silver-Russell , Femenino , Embarazo , Humanos , Síndrome de Silver-Russell/genética , Función Ejecutiva , Teorema de Bayes , Metilación , Disomía Uniparental , Metilación de ADN , Impresión Genómica , FenotipoRESUMEN
BACKGROUND: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies. RESULTS: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy. CONCLUSION: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.
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Raquitismo Hipofosfatémico Familiar , Hormona de Crecimiento Humana , Niño , Humanos , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Hormona del Crecimiento , Calcio , Factores de Crecimiento de Fibroblastos , Proteínas Recombinantes , FosfatosRESUMEN
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.
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Endocrinología , Medicina Nuclear , Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Niño , Adolescente , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/terapia , Nódulo Tiroideo/patología , Cintigrafía , Consenso , Neoplasias de la Tiroides/patologíaRESUMEN
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
Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Asunto(s)
Diabetes Mellitus Tipo 2 , Síndrome de Turner , Adulto , Cromosomas Humanos X/genética , Femenino , Humanos , Cariotipo , Cariotipificación , Síndrome de Turner/diagnóstico , Síndrome de Turner/genética , Síndrome de Turner/terapiaRESUMEN
CONTEXT: Resistance to thyroid hormone ß syndrome (RTHß) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHß phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. CASE DESCRIPTION: The patient is a 52-year-old woman with clinical and biological signs of RTHß. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHß syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949Gâ >â A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. CONCLUSIONS: We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHß syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHß, thus avoiding patient mismanagement.