[Assessment and management of gender dysphoria in children and adolescents]. / Évaluation et prise en charge d'une dysphorie de genre chez l'enfant et l'adolescent.

Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines.

Dental caries and enamelin haplotype.

In the literature, the enamelin gene ENAM has been repeatedly designated as a possible candidate for caries susceptibility. Here, we checked whether ENAM variants could increase caries susceptibility. To this aim, we sequenced coding exons and exon-intron boundaries of ENAM in 250 children with a severe caries phenotype and in 149 caries-free patients from 9 French hospital groups. In total, 23 single-nucleotide polymorphisms (SNPs) were found, but none appeared to be responsible for a direct change of ENAM function. Six SNPs had a high minor allele frequency (MAF) and 6 others were identified for the first time. Statistical and evolutionary analyses showed that none of these SNPs was associated with caries susceptibility or caries protection when studied separately and challenged with environmental factors. However, haplotype interaction analysis showed that the presence, in a same variant, of 2 exonic SNPs (rs7671281 and rs3796704; MAF 0.12 and 0.10, respectively), both changing an amino acid in the protein region encoded by exon 10 (p.I648T and p.R763Q, respectively), increased caries susceptibility 2.66-fold independent of the environmental risk factors. These findings support ENAM as a gene candidate for caries susceptibility in the studied population.

[Effect of SSRIs on bone metabolism]. / Effet des inhibiteurs sélectifs de recapture de la sérotonine (ISRS) sur la croissance osseuse : une revue de la littérature.

INTRODUCTION: SSRIs have been shown to affect bone health in adults, but this has been poorly studied in children. Given the frequency of SSRI prescription in children and adolescents, it is crucial to evaluate the impact of SSRIs on bone growth because the bone mass attained early in life is the most important predictor of a normal bone constitution. Experimental studies have demonstrated a direct functional role of serotonin in bone metabolism, independently of hyperprolactinemia or growth hormone levels. We have reviewed the literature on serotonin and bone metabolism, including experimental studies, clinical studies in adults as well as in the pediatric population. EXPERIMENTAL STUDIES: Experimental studies have shown that 5-HT transporter (5-HTT) is expressed in all kind of bone cells and is highly specific of the 5-HT recapture. 5-HTT inhibition by the SSRIs in these cells affects their function in vitro. Even though a few studies have suggested exposure to SSRIs could be beneficial by an anabolic effect on the trabecular bone, more concluding studies have demonstrated that SSRIs negatively affect bone growth, resulting in a specific bone phenotype including a reduction in bone mass, an altered bone architecture, and decreased mechanical properties. This phenotype is most probably the consequence of a decrease in bone formation, rather than an increase in bone resorption and is a direct and dose-dependent effect. However, many aspects of this bone effect of 5-HTT inhibition need to be further clarified, including the signal ways for 5-HTT and 5-HT receptors, origins of 5-HT in bone, and methods to isolate the inhibitory effect of 5-HTT specifically on bone. CLINICAL STUDIES: Metabolic and neuroendocrine side effects have been documented in children and adolescents taking SSRIs but the specific and direct effect of these molecules on bone metabolism has been poorly studied in this population. In adults, clinical studies have shown an association between the use of SSRIs and bone demineralization as well as reduction in bone mass, especially in the elderly and post-menopausal women. However, depression itself has been associated with a lower bone mass and increased risk of osteoporosis. In children, case reports show a decrease in growth due to a decreased secretion of growth hormone, but not by a direct effect. One cross-sectional study suggests a decrease in bone mass following SSRI treatment that is independent of variation in prolactin levels, but without elevation of fracture risk. These results, however, need to be replicated in further studies. CONCLUSION: Our review shows that experimental studies have demonstrated the implication of the serotonin system in bone metabolism. Mice with genetic disruption of 5-HTT have a bone phenotype of decreased bone mass, altered architecture, and decreased mechanical properties. Clinical studies exploring the effect of SSRIs on bone metabolism are scarce in children. However, results in adults tend to show a deleterious effect in the elderly. Regarding the frequency of SSRI prescription in the pediatric population, it is becoming urgent to better explore the effect of SSRIs on bone growth of children, as it can have major implications on the ulterior follow-up and on the precautions to take.

Common SNPs of AmelogeninX (AMELX) and dental caries susceptibility.

Genetic approaches have shown that several genes could modify caries susceptibility; AmelogeninX (AMELX) has been repeatedly designated. Here, we hypothesized that AMELX mutations resulting in discrete changes of enamel microstructure may be found in children with a severe caries phenotype. In parallel, possible AMELX mutations that could explain resistance to caries may be found in caries-free patients. In this study, coding exons of AMELX and exon-intron boundaries were sequenced in 399 individuals with extensive caries (250) or caries-free (149) individuals from nine French hospital groups. No mutation responsible for a direct change of amelogenin function was identified. Seven single-nucleotide polymorphisms (SNPs) were found, 3 presenting a high allele frequency, and 1 being detected for the first time. Three SNPs were located in coding regions, 2 of them being non-synonymous. Both evolutionary and statistical analyses showed that none of these SNPs was associated with caries susceptibility, suggesting that AMELX is not a gene candidate in our studied population.

Continuous subcutaneous insulin infusion allows tolerance induction and diabetes treatment in a type 1 diabetic child with insulin allergy.

AIM: Insulin allergy is a rare but serious and challenging condition in patients with type 1 diabetes (T1D). This is a case report of an 8-year-old boy with T1D and an allergy to insulin. CASE REPORT: Three months after being diagnosed with T1D, the patient developed progressive skin reactions to insulin, characterized by small 1.5-cm pruritic wheals at injection sites that persisted for several days. Seven months after diagnosis, he experienced two episodes of generalized urticaria with systemic symptoms that were seen within a few seconds of insulin injection. Examination revealed lipoatrophy of the thighs. Intradermal skin tests were positive for protamine, glargine and lispro. The patient was started on a continuous subcutaneous insulin infusion (CSII) tolerance induction protocol, consisting of a very low basal rate that was progressively increased, with the first bolus given under medical supervision, and was well tolerated for 4 months. After this period of time, the skin wheals reappeared, localized to the infusion sites, but without urticaria or any other generalized reactions. Intradermal skin tests were repeated and were again positive. Serum insulin-specific IgE measured 30 months after the first allergic reactions were positive. After 3 years, pump therapy is ongoing and blood glucose control has remained relatively good (HbA1c 7.6%). CONCLUSION: In T1D children with insulin allergy, CSII can successfully be used to both induce insulin tolerance and allow diabetes insulin therapy, although insulin desensitization cannot always be fully achieved. The induction protocol was easily manageable partly due to the "honeymoon" period that the patient was still in, but it should nonetheless be used even when the patient has higher insulin requirements.

Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.

Phenotypic homogeneity and genotypic variability in a large series of congenital isolated ACTH-deficiency patients with TPIT gene mutations.

CONTEXT: Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause. OBJECTIVE: We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease. DESIGN: Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed. RESULTS: We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects. CONCLUSION: TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.

[Turner Syndrome: what's new in medical care?]. / Le syndrome de Turner : quoi de neuf dans la prise en charge ?

Turner syndrome is a rare genetic disorder, affecting approximately one in 2500 live-born female, due to total or partial absence of the X chromosome. Typical clinical features are short stature and premature ovarian failure and less constantly phenotypic particularities such as congenital malformations, acquired cardiovascular, otological (hearing impairment), autoimmune and metabolic pathologies. The phenotype is highly variable with slight or even normal phenotype. Several studies have shown that growth hormone treatment improves adult height. The possibility of pregnancies after oocyte donation highlights the high risk of these pregnancies requiring a careful follow-up, especially in terms of cardiovascular issues. Although the quality of life seems similar to the normal population, the presence of cardiovascular and otological diseases, and delayed feminisation are associated with an impaired quality of life. Early diagnosis and regular screening for potentials associated complications are essential in the medical follow-up of these patients. The recent publication of recommendations should lead to an optimization and harmonisation of the medical practices and follow-up from paediatric age to adulthood, a lowering morbidity and self-esteem improvement. The interest of ovarian cryopreservation at an early age in these patients is under investigation.

Growth hormone treatment before the age of 4 years prevents short stature in young girls with Turner syndrome.

OBJECTIVE: Adult height deficit seen in Turner syndrome (TS) originates, in part, from growth retardation in utero and throughout the first 3 years of life. Earlier diagnosis enables earlier therapeutic intervention, such as with recombinant human GH (r-hGH), which may help to prevent growth retardation. In this open-label, multicentre phase III study, we investigated efficacy and safety in r-hGH treatment in young girls with TS. SUBJECTS AND METHODS: Girls (n=61) aged <4 years with TS receiving 0.035-0.05 mg/kg per day r-hGH for 4 years were compared with an historical control group (n=51) comprising untreated, age- and height-matched girls with TS. The main outcome measure was change in height SDS (H-SDS). Other measures included changes in height velocity SDS, IGF1 levels and glucose metabolism. RESULTS: After 4 years, a gain in mean H-SDS of 1.0 SDS (from -2.33±0.73 to -1.35±0.86 SDS) was observed with r-hGH treatment, in contrast to the decrease in mean H-SDS of 0.3 SDS in the control group (from -2.09±0.81 to -2.44±0.73 SDS; P<0.0001). r-hGH treatment was the main predictor of H-SDS gain and accounted for 52% of variability (multivariate analysis). r-hGH was well tolerated. As expected, IGF1 levels rose with treatment. A case of transient glucose intolerance resolved after dietary adaptation. CONCLUSION: Early treatment with r-hGH helps to prevent natural evolution towards short stature in most girls with TS. IGF1 levels and glucose metabolism should be monitored routinely during r-hGH therapy.

Child health, developmental plasticity, and epigenetic programming.

Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.

Risk of autoimmune diabetes in APECED: association with short alleles of the 5'insulin VNTR.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disease causing a wide spectrum of autoimmune dysfunction potentially including diabetes of an autoimmune etiology. We have previously described a pair of discordant APECED siblings and pointed to a possible role of 5'insulin variable number of tandem repeats (VNTR) locus IDDM2 in the appearance of diabetes within this disease. In vitro studies have previously suggested that class I VNTR alleles were associated with decreased fetal thymic insulin expression. We genotyped the 5'INS VNTR locus and several flanking 11p15.5 markers in 50 Finnish APECED subjects and explored the possible contribution of IDDM2 in the development of diabetes. The shorter 5'INS VNTR class I alleles (<35 repeats) were more prevalent in the diabetic Finnish APECED subjects than in non-diabetic APECED subjects. Logistic regression analysis revealed that having 1 short (<35) VNTR allele did not increase the risk of developing diabetes (95% CI 0.6-27.0), whereas having 2 short alleles conferred a 43.5-fold increased risk (95% CI 3.0-634.6). We conclude that short 5'INS VNTR class I alleles play a role in susceptibility to autoimmune diabetes in the context of APECED.

Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B.

CONTEXT: Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy. OBJECTIVE: To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome. DESIGN AND SETTING: A university hospital-based prospective study from 2001 to 2008. SUBJECTS AND METHODS: Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening. RESULTS: Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC. CONCLUSION: Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents.

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappaB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.