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Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and the most common preventable cause of development delay and growth failure if diagnosed and treated early. The thyroid is the first endocrine gland to develop during embryonic life and to be recognizable in humans. Thyroid development and maturation can be divided into 2 phases: a first phase of embryogenesis and a second phase of folliculogenesis and differentiation with thyroid hormone production at the final steps. Regulation of the thyroid function requires normal development of the hypothalamic–pituitary–thyroid axis, which occurs during the embryonic and neonatal period. Defects in any of steps of thyroid development, differentiation, and regulation lead to permanent CH. Newborn screening programs, established in only one-third of countries worldwide, detect CH and are cost-effective and highly sensitive and specific. During the last decade, epidemiology of CH has changed with increased frequency of thyroid in situ in primary CH. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. However, a molecular cause is identified in only 5% of CH due to thyroid dysgenesis. The purpose of this article is to describe the clinical approach to the child with CH, focusing on diagnostic work-up and future challenges on optimizing thyroid replacement therapy and regenerative medicine. The review is written from the perspective of the case of 2 girls referred for CH after newborn screening and diagnosed with thyroid ectopy. The genetic work-up revealed novel mutations in TUBB1 gene, associated with large platelets and abnormal platelet physiology.

ContextEndocrine complications are common in pediatric brain tumor patients.ObjectiveTo describe hypothalamic–pituitary–gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment.MethodsWe retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded.ResultsAmong patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency.ConclusionTumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

ContextCraniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma.ObjectiveTo evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence).MethodsRetrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (12-month group and in the ResultsIn the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment.ConclusionsNo association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Context Endocrine complications are common in pediatric brain tumor patients. Objective We aimed to describe the endocrine follow-up of patients with primary brain tumors. Methods This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Results Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (−0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (−1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). Conclusion We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Context Early treatment is essential to avoid the cardiac complication of neonatal hyperthyroidism (NH). Our results have direct implications for clinical care. Objective NH can cause potentially fatal neonatal thyrotoxicosis. Here, we have evaluated the feasibility of neonatal hyperthyroidism screening using the thyroid-stimulating hormone value in dried blood collected routinely on filter paper on the third postnatal day of life for congenital hypothyroidism screening. Methods Retrospective case–control study. Cases were identified using data from our previously published study of 280 000 infants born in 10 maternity units in France in 2007-2014. Controls were identified among the 1 362 564 infants born in the Ile-de-France region during the same period. Results A screening thyroid-stimulating hormone level below 0.18 mIU/L on the third postnatal day had 71% (95% CI 44-90%) sensitivity, 99% (95% CI 99-100%) specificity, 81% (95% CI 74-86%) positive predictive value, and 98% (95% CI 97-99%) negative predictive value for detecting severe NH. By univariate regression analysis, the screening thyroid-stimulating hormone value was the strongest predictor of NH (P < .00001), with an area under the receiver-operating characteristics curve of 0.98 (95% CI 0.95-1.0). Expected frequencies were not significantly different from observed frequencies (Hosmer–Lemeshow test, P = .99). Conclusion The screening thyroid-stimulating hormone test can be used to detect severe NH, the optimal cut-off being 0.18 mIU/L. The additional cost compared with screening for congenital hypothyroidism would be small. Infants with neonatal hyperthyroidism would benefit from an earlier diagnosis with treatment initiation at the presymptomatic stage in many cases, ensuring optimal outcomes.

ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000–60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3–52 years)) and 47 males (median age, 19 years (3–45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.

BackgroundPerinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied.MethodsAdrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1–exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells.ResultsAt week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells.ConclusionsLopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation.Clinical Trials RegistrationNCT00640263

The most common thyroid abnormality among Down syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onward, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by bacterial artificial chromosome engineering (mBACTgDyrk1A), have 3 copies of the Dyrk1A gene. The objective is to determine whether this transgenic Dyrk1A (Dyrk1A+/++) mouse is an adequate murine model for the study of thyroid dysgenesis in DS. Embryonic thyroid development from embryonic day 13.5 (E13.5) to E17.5 was analyzed in wild-type (WT) and Dyrk1A+/++ mice by immunofluorescence with anti-Nkx2–1, anti-thyroglobulin, and anti-T4 antibodies, markers of early thyroid development, hormonogenesis, and final differentiation, respectively. The expression of transcription factors Nkx2–1, Pax8, and Foxe1 involved in thyroidogenesis were studied by quantitative RT-PCR at the same embryonic stages. We then compared the adult phenotype at 8 to 12 weeks in Dyrk1A+/++ and WT mice for T4 and TSH levels, thyroidal weight, and histological analysis. Regarding thyroidal development, at E15.5, Dyrk1A+/++ thyroid lobes are double the size of WT thyroids (P = .01), but the thyroglobulin stained surface in Dyrk1A+/++ thyroids is less than a third as large at E17.5 (P = .04) and their differentiated follicular surface half the size (P = .004). We also observed a significant increase in Nkx2–1, Foxe1, and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A+/++ embryonic thyroids. Dyrk1A+/++ young adult mice have significantly lower plasma T4 (2.4 ng/mL versus WT, 3.7 ng/mL; P = 0.019) and nonsignificantly higher plasma TSH (114 mUI/L versus WT, 73mUI/L; P = .09). In addition, their thyroids are significantly heavier (P = .04) and exhibit large disorganized regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid phenotype is probably a result of embryogenetic impairment. The Dyrk1A+/++ mouse can be considered a suitable study model for thyroid dysgenesis in DS.

Down syndrome is characterized by a high prevalence of thyroid dysfunction during childhood. In this paper, we review the different kinds of thyroid dysfunction that occur excluding those of autoimmune origin: congenital hypothyroidism (elevated plasma TSH with low plasma T4 occurring at birth usually detected by neonatal screening), subclinical hypothyroidism (elevated plasma TSH with plasma T4 in the normal range, which can be congenital or acquired) and acquired primary hypothyroidism (elevated plasma TSH and low plasma T4 occurring after birth). These dysfunctions, while not due to autoimmunity, are of thyroidal origin. However, the mechanisms leading to these different thyroidal abnormalities have not been clearly defined; in particular, it is difficult to determine whether the different types of dysfunction have a common cause, or if the causes are distinct. Treatment is prescribed according to the type of thyroidal abnormality.

Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.

Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine-sufficient regions and includes a spectrum of developmental anomalies. The genetic components of TD are complex. Although a sporadic disease, advances in developmental biology have revealed monogenetic forms of TD. Inheritance is not based on a simple Mendelian pattern and additional genetic elements might contribute to the phenotypic spectrum. This article summarizes the key steps of normal thyroid development and provides an update on responsible genes and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge of TD.

Type 2 diabetes is caused by a limited capacity of insulin-producing pancreatic β cells to increase their mass and function in response to insulin resistance. The signaling pathways that positively regulate functional β cell mass have not been fully elucidated. DYRK1A (also called minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. A significant amount of data implicates DYRK1A in brain growth and Down syndrome, and recent data indicate that Dyrk1A haploinsufficient mice have a low functional β cell mass. Here we ask whether Dyrk1A upregulation could be a way to increase functional β cell mass. We used mice overexpressing Dyrk1A under the control of its own regulatory sequences (mBACTgDyrk1A). These mice exhibit decreased glucose levels and hyperinsulinemia in the fasting state. Improved glucose tolerance is observed in these mice as early as 4 weeks of age. Upregulation of Dyrk1A in β cells induces expansion of β cell mass through increased proliferation and cell size. Importantly, mBACTgDyrk1A mice are protected against high-fat-diet-induced β cell failure through increase in β cell mass and insulin sensitivity. These studies show the crucial role of the DYRK1A pathway in the regulation of β cell mass and carbohydrate metabolism in vivo. Activating the DYRK1A pathway could thus represent an innovative way to increase functional β cell mass.

Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth-Lazarus syndrome: congenital hypothyroidism (CH) with thyroid dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype.FOXE1 was sequenced in eight patients with thyroid dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression.We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy with a typical phenotype (athyreosis, cleft palate, and partial choanal atresia). This new mutation located within the forkhead domain was inherited from the heterozygous healthy consanguineous parents. In vitro functional studies in HEK293 cells showed that this mutant gene enhanced the activity of the TG and TPO gene promoters (1.5-fold and 1.7-fold respectively vs. wild type FOXE1; p0.05), unlike the five mutations previously reported in Bamforth-Lazarus syndrome. The gain-of-function effect of the FOXE1-p.R73S mutant gene was confirmed by an increase in endogenous TG production in primary human thyrocytes.We identified a new homozygous FOXE1 mutation responsible for enhanced expression of the TG and TPO genes in a boy whose phenotype is similar to that reported previously in patients with loss-of-function FOXE1 mutations. This finding further delineates the role for FOXE1 in both thyroid and palate development, and shows that enhanced gene activity should be considered among the mechanisms underlying Bamforth-Lazarus syndrome.

Aims/hypothesis: Growth factors and nutrients are important regulators of pancreatic beta cell mass and function. However, the signalling pathways by which these factors modulate these processes have not yet been fully elucidated. DYRK1A (also named minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been conserved across evolution. A significant amount of data implicates DYRK1A in brain growth and function, as well as in neurodegenerative processes in Alzheimer's disease and Down's syndrome. We investigated here whether DYRK1A would be an attractive candidate for beta cell growth modulation. Methods: To study the role of DYRK1A in beta cell growth, we used Dyrk1a-deficient mice. Results: We show that DYRK1A is expressed in pancreatic islets and provide evidence that changes in Dyrk1a gene dosage in mice strongly modulate glycaemia and circulating insulin levels. Specifically, Dyrk1a-haploinsufficient mice show severe glucose intolerance, reduced beta cell mass and decreased beta cell proliferation. Conclusions/interpretation: Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile. © 2014 Springer-Verlag Berlin Heidelberg., The research leading to these results received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115439, comprising financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies. The RS laboratory belongs to the Laboratoire d’Excellence consortium Revive. This work was supported by grants from Inserm ‘Junior 5-year Contract’ (LR)

Background: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). Aims: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. Methods: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. Results: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. Conclusion: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France.To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir.Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine.Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency.Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P.001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P.001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P.001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Introduction Les facteurs de croissance et les nutriments sont des regulateurs majeurs de la masse et de la fonction des cellules beta pancreatiques. Les voies de signalisation par lesquelles ces facteurs de croissance et nutriments agissent ne sont pas completement elucidees. DYRK1A (egalement nommee MNB/ minibrain) est un membre d’un groupe de kinases fortement conservees a travers l’evolution. Des donnees recentes associent DYRK1A a la croissance et au fonctionnement du cerveau, ainsi qu’a la neurodegenerescence et au syndrome de Down. Nos travaux decrits ci-dessous demontrent que DYRK1A est un candidat d’interet pour controler la croissance de la masse des cellules beta. Materiels et methodes Pour etudier le role de Dyrk1A sur la croissance des cellules beta, nous avons utilise des souris deficientes ou surexprimant Dyrk1A. Resultats Nous apportons la preuve que des changements dans l’expression genique de Dyrk1A chez la souris modulent les taux sanguins d’insuline. Des experiences sur des souris haplo-insuffisantes pour DYRK1A montrent une severe intolerance au glucose associee a une reduction de la masse des cellules beta, due a une diminution de leur proliferation. En miroir, les souris surexprimant Dyrk1A presentent une hypoglycemie associee a une hyperinsulinemie due a une expansion de la masse des cellules beta. Cette surexpression de Dyrk1A a pour resultat une augmentation de la proliferation et de la taille de la cellule beta. Enfin, la surexpression de Dyrk1A protege les souris d’une induction du diabete suite a un regime gras. Conclusion En conclusion, nos donnees suggerent que Dyrk1A est une kinase majeure pour le controle de la proliferation des cellules beta de souris. Des modulateurs chimiques de cette kinase pourraient permettre d’augmenter la masse de cellules beta.