Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

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.

Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction.

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.

Diagnosis and management of congenital hypopituitarism in children.

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.

Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.

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.

Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP).

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.

Factors Associated With Weight Loss After Laparoscopic Adjustable Gastric Banding in Adolescents With Severe Obesity.

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.

Identification of novel compound heterozygous variants in the SLC30A7 (ZNT7) gene in two French brothers with stunted growth, testicular hypoplasia and bone marrow failure.

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.

Growth pattern in children with X-linked hypophosphatemia treated with burosumab and growth hormone.

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.

Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype.

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.

SFE-AFCE-SFMN 2022 Consensus on the management of thyroid nodules : Thyroid nodules in children.

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.

Clinically Symptomatic Resistance to Thyroid Hormone ß Syndrome Because of THRB Gene Mosaicism.

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.949G > 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.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Lower Circulating Sertoli and Leydig Cell Hormone Levels During Puberty in Obese Boys: A Cross-sectional Study.

CONTEXT: Alterations in semen characteristics and circulating Sertoli and Leydig cell hormones have been described in obese male adults. Whether hormonal alterations occur before adulthood has not been fully evaluated. OBJECTIVE: We describe circulating Sertoli and Leydig cell hormone levels in overweight-obese (ow/ob) boys through childhood and adolescence in a cross-sectional study. METHODS: Monocentric study in the Pediatric Endocrinology Unit of Angers University Hospital. Three hundred and fifty-one obese and overweight boys aged 5-19 years underwent physical examination, dual-energy X-ray absorptiometry for body composition, oral glucose tolerance test on insulin and glucose, and measurements of follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone (AMH), inhibin B, testosterone, and estradiol. Hormonal levels were compared with normative data obtained from 652 healthy nonoverweight nonobese boys of similar age or Tanner stage. RESULTS: Median inhibin B and testosterone levels during puberty were significantly lower in ow/ob than in healthy boys (1) from age >12 years and thereafter for inhibin B, and (2) from age >14 years and thereafter for testosterone. At Tanner stages 4 and 5, 26%, 31%, and 18% of inhibin B, testosterone, and AMH values were below the 5th percentile in ow/ob subjects (P < .01). In multiple regression analyses, estradiol and total bone mineral density Z-score were negative predictors of inhibin B, fat mass percentage was a negative predictor of testosterone, and insulin was a negative predictor of AMH. CONCLUSION: Lower Sertoli and Leydig cell hormone levels during puberty were observed in the ow/ob boys.

Position statement on the diagnosis and management of premature/primary ovarian insufficiency (except Turner Syndrome).

Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.

Cardiac complications of thyroid hormone resistance syndromes.

Thyroid hormones exert their action by binding to their thyroid hormone receptors among other mechanisms. They are involved in different cardiac functions, including contractility and rhythm. The mutation of thyroid hormone receptor ß is the main cause of thyroid hormone resistance. The cardiac phenotype of mutated patients has been studied in several cohorts of patients with different mutations. Tachycardia, palpitation and cardiac arrhythmia frequently appear; atrial flutter/fibrillation is found in up to 20%. Cardiac systolic and diastolic functions are impaired compared to hyperthyroid or euthyroid subjects, but cases of heart failure have not been reported. No correlation between genotype and cardiac phenotype has been found. Patients with a mutation of thyroid hormone receptor α frequently present bradycardia and systolic and diastolic functions that are similar to those of hypothyroid subjects. Levothyroxine treatment partly improves these parameters.

GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

STUDY QUESTION: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? SUMMARY ANSWER: Both parameters lack the specificity to discriminate CDGP from CHH. WHAT IS KNOWN ALREADY: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. STUDY DESIGN, SIZE, DURATION: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. MAIN RESULTS AND THE ROLE OF CHANCE: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. LIMITATIONS, REASONS FOR CAUTION: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. WIDER IMPLICATIONS OF THE FINDINGS: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Forum theater staging of difficult encounters with patients to increase empathy in students: evaluation of efficacy at The University of Angers Medical School.

BACKGROUND: Physician empathy has been associated with improved clinical outcomes and lower physician burnout. We evaluated whether forum theater (FT), a form of applied drama that allows participants to enter the performance and represent the actions associated with emotions, would foster empathy in medical students, and which underlying variables would be associated to empathy scores. METHODS: Three classes totaling 488 fourth-year medical students participated in the study. Forum theater was used to explore difficult encounters with patients and family members: announcement of cancer, fall at home of an elderly person requiring hospitalization, appointment with a patient suffering from depression, announcement of diabetes in an adolescent. The first scene was played by actors in front of a group of students, then audience members were asked to enter the performance and, by taking over the role of the "physician-actor," to explore alternative interactions. All the students followed two sessions as actors and observers in random order and were randomly assigned to FT sessions after 36 or 56 weeks of clinical rotations. They completed the Jefferson Scale of Physician Empathy (JFSE) anonymously. RESULTS: Students were 22.1 ± 1.5 years old (43% males). Empathy scores increased after each session: 102.0 ± 9.8 before the sessions, 106.3 ± 9.8 after session 1 and 107.8 ± 11.5 after session 2 (p <  0.05). In regression models, gender (F vs. M, + 3.0 ± 1.0, p <  0.001) and position in the session (actor vs. observer, + 2.1 ± 1.0, p < 0.05) were significant determinants of JFSE scores, whereas age, session theme, and duration of clinical rotation were not. CONCLUSION: Being an actor in forum theater was a valuable tool for enhancing empathy scores in medical students.

Neonatal and neurodevelopmental outcomes in preterm infants according to maternal body mass index: A prospective cohort study.

OBJECTIVE: Maternal obesity is associated with an increase in maternal, foetal and neonatal morbidity and mortality. The aim of our study was to evaluate the relationships between maternal pre-pregnancy body mass index and (1) neonatal outcome in preterm infants, and (2) neurodevelopmental outcome at 2 years of corrected age. METHOD: We conducted a single-centre cohort study. Infants born between 24+0 and 33+6 weeks of gestation between January 2009 and December 2013, hospitalised in the neonatal intensive care unit of Angers University Hospital, and with available data regarding maternal pre-pregnancy body mass index were eligible. Three groups were defined according to maternal body mass index: normal (n = 418), overweight (n = 136) and obese (n = 89). The primary outcome was neurodevelopment at 2 years of corrected age. Children with a non-optimal neuromotor and/or psychomotor assessment and/or a sensory disability were regarded as having a "non-optimal neurodevelopmental outcome". Neuromotor function was regarded as non-optimal when cerebral palsy was present or when the clinical examination revealed neurological signs of abnormal muscular tone. Psychomotor assessment was regarded as non-optimal if the revised Brunet-Lézine test was < 85 or when the overall score in the parental Ages and Stages Questionnaire (ASQ) was < 185. Finally, sensory disabilities such as blindness and children who required a hearing aid were taken into account. The secondary outcome was the composite criteria of neonatal complications. Multivariable analysis included the following variables: mother's age, gestational age, smoking during pregnancy, magnesium sulphate and steroid treatment during pregnancy, twin status, gender, socioeconomic status and social security benefits for those with low incomes. RESULTS: The study population was composed of 643 preterm infants. Among them, 520 were assessed at 2 years. There was no difference in the proportion of infants with non-optimal neurodevelopmental outcomes between the three groups (16.6% for obese, 13.5% for overweight, 16.9% for normal body mass index mothers; p = 0.73). According to multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neuro-development at 2 years (adjusted OR = 0.84 [0.40-1.76] for obese, adjusted OR = 0.83 [0.43-1.59] for overweight mothers). There was no difference in the proportion of preterm infants with a non-optimal composite criterion of neonatal complications between the three groups. In the multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neonatal outcomes (adjusted OR = 0.95 [0.49-1.83] for obese, adjusted OR = 1.18 [0.69-2.01] for overweight mothers). CONCLUSION: In this large prospective cohort of preterm infants born before 34 weeks of gestation, we found no relationship between maternal body mass index and neurodevelopmental outcomes at 2 years of corrected age and no relationship between maternal body mass index and neonatal outcomes. Other prematurity-related factors may be more relevant for neurodevelopmental outcome than the mother's pre-pregnancy BMI.

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

Mitotane (op'DDD) restores growth and puberty in nine children with Cushing's disease.

To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing's disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (-3.8 (±0.3) vs -0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.