Publications by authors named "Marc Nicolino"

66 Publications

Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide.

J Pediatr Endocrinol Metab 2021 Mar 4. Epub 2021 Mar 4.

Department of Pediatric Endocrinology, HFME, Hospices Civils de Lyon, Bron, France.

Objectives: Serious hyperinsulinemic hypoglycemia (HH) is generally the main initial symptom of hyperinsulinism. Epilepsy, without any overt feature of hypoglycemia, might be a very rare initial presentation of late-onset isolated hyperinsulinism.

Case Presentation: We describe a case of late-onset HH in a 15-year-old boy with a history of idiopathic generalized epilepsy, now named genetic generalized epilepsy (IGE/GGE), beginning with a tonic-clonic seizure at the age of 11 years. Subsequently, absences with rare eyelid myoclonia were recorded on electroencephalogram (EEG), followed by episodes of impaired consciousness with facial myoclonia. Neurological status was normal except attention-deficit hyperactivity disorder (ADHD). At the age of 15 years, an episode of slight alteration of consciousness with neurovegetative signs could be recorded, which did not correspond to an absence status. Hypoglycemia due to hyperinsulinism was documented (clinically, biologically, and genetically). Diazoxide treatment resolved the glycopenic symptoms, the non-hypoglycemic seizures and normalized brain electrical activity allowing complete withdrawal of antiepileptic medication.

Conclusions: Epilepsy can be a very rare initial feature of HH starting in childhood. The occurrence of atypical features in the context of GGE as "absence statuses" with unusual vegetative symptoms and facial myoclonia might be suggestive for HH. Careful assessment and specific treatment are necessary to prevent hyperinsulinism related brain damage. Our case showed that diazoxide might also resolve seizures and normalize EEG.
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http://dx.doi.org/10.1515/jpem-2020-0381DOI Listing
March 2021

DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes.

Eur J Endocrinol 2021 Mar;184(3):459-472

ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.

Objective: DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome.

Methods: Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined.

Results: The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA.

Conclusions: This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.
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http://dx.doi.org/10.1530/EJE-20-0636DOI Listing
March 2021

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

Clin Endocrinol (Oxf) 2021 Feb 21;94(2):277-289. Epub 2020 Dec 21.

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Faculté des Sciences médicales et paramédicales, Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Context: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism.

Aims: To describe main phenotype patterns and their evolution through life.

Design: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.

Results: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.

Conclusion: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.
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http://dx.doi.org/10.1111/cen.14355DOI Listing
February 2021

Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome.

Eur J Med Genet 2020 Nov 28;63(11):104044. Epub 2020 Aug 28.

Service de Génétique, Hospices Civils de Lyon, Bron, France; Equipe GENDEV, CRNL, INSERM U1028 CNRS UMR5292 Université Claude Bernard Lyon 1, Lyon, France. Electronic address:

Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy. Three genes, BUB1B, CEP57 and TRIP13, are involved in this syndrome. Only 7 patients carrying pathogenic variants in CEP57 are reported to date. Here we report two adult brothers born to Moroccan related parents, who presented with intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, learning disabilities, skeletal anomalies with thumb hypoplasia and dental abnormalities. Both brothers have mosaic variegated aneuploidies on blood karyotype. A previously reported homozygous 11 bp duplication was identified in CEP57 in the two brothers. We propose that a FoSTeS (Fork Stalling and Template Switching) mechanism could be involved in the occurrence of this duplication. This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly.
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http://dx.doi.org/10.1016/j.ejmg.2020.104044DOI Listing
November 2020

Effects of advanced carbohydrate counting on glucose control and quality of life in children with type 1 diabetes.

Pediatr Diabetes 2020 Nov 3;21(7):1240-1248. Epub 2020 Aug 3.

Pediatric Diabetology, University Hospital, Angers, France.

Objective: The effect of advanced carbohydrate counting (ACC) on metabolic and quality of life (QOL) outcomes is uncertain in children with type 1 diabetes. Our aim was to determine whether ACC would improve HbA1c and QOL scores as compared with standard nutrition in this population.

Methods: We randomized 87 patients using pump and rapid-acting analogs in a 1 year randomized multicenter study (age 9.6 ± 3.5 years, diabetes duration 4.6 ± 2.7 years, HbA1c 7.8 ± 0.5% [62 ± 5 mmol/mol]). The ACC group received CC education and the control group received traditional dietary education. HbA1c was measured every 3 months. At 0 and 1 year, general, diabetes-specific, and diet-related QOL were respectively assessed by the KIDSCREEN and WHO-5 questionnaires, the diabetes-specific module of the DISABKIDS, and the diet restriction items of the DSQOLS.

Results: Mean HbA1c was lower in the ACC than the control group at 3 months (P < .05) and tended to be lower at 6 months (P = .10), 9 months (P = .10), but not at 12 months. The mean of individual average HbA1c during the one-year study period (from M3 to M12) was 7.63 ± 0.43 in the ACC vs 7.85 ± 0.47% in the control group (60 ± 5 vs 62 ± 5 mmol/mol)(P < .05). ACC was associated with significantly higher scores at 1 year on the KIDSCREEN children's psychological scale and the KIDSCREEN parents' physical scale, the DISABKIDS children's treatment scale, and the children's and parents' dietary restriction scales of the DSQOLS (indicating better QOL or lower perceived diet restriction).

Conclusions: ACC may be associated with small improvements in metabolic control and QOL scores in children.
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http://dx.doi.org/10.1111/pedi.13076DOI Listing
November 2020

Reference values for the external genitalia of full-term and pre-term female neonates.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 19;106(1):39-44. Epub 2020 Jun 19.

Service d'endocrinologie pédiatrique, Hospices Civils de Lyon, Lyon, France.

Background And Objectives: Identifying virilisation of the genitalia in female newborns early during the neonatal period is important to diagnose pathologies. However, there is no clear threshold for clitoromegaly or for the anogenital ratio. The objective of this study was to define reference values for the external genitalia of full-term and pre-term female neonates.

Design: This was a prospective study of all females born in the study centre between May 2014 and July 2016. Clitoral length and anogenital ratio were measured in 619 newborns with a gestational age of 24+2 to 41+3 weeks during their first 3 days of life. Associations between the values at day 3 and gestational age, birth weight and other newborn characteristics were examined by linear regression.

Results: The mean clitoral length at day 3 of life was 3.69±1.53 mm (n=551; 95th percentile, 6.5 mm; maximum, 8 mm), and the mean anogenital ratio was 0.42±0.09 (95th percentile, 0.58). There was no significant variation with gestational age or birth weight, and no significant difference between the results at day 0 and day 3.

Conclusion: These results suggest that clitoromegaly can be defined as a clitoral length >6.5 mm. Values ≥8 mm should prompt further investigations. An anogenital ratio >0.6 should be considered a sign of virilisation. Since clitoral size does not vary with gestational age or birth weight, clitoromegaly should not be attributed to prematurity.
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http://dx.doi.org/10.1136/archdischild-2019-318090DOI Listing
January 2021

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations.

Horm Res Paediatr 2020 26;93(1):30-39. Epub 2020 May 26.

Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d'Endocrinologie Pédiatrique, Bron, France.

Background: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies.

Methods: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation.

Results: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism.

Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.
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http://dx.doi.org/10.1159/000507249DOI Listing
May 2020

A systematic review of non-genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis.

Diabetes Metab Res Rev 2018 11 13;34(8):e3051. Epub 2018 Sep 13.

Inserm DISC, siège, Paris, France.

Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic βcells. Although all T1D patients require daily administration of exogenous insulin, their insulin requirement to achieve good glycaemic control may vary significantly. Glycated haemoglobin (HbA1c) level represents a stable indicator of glycaemic control and is a reliable predictor of long-term complications of T1D. The purpose of this article is to systematically review the role of non-genetic predictors and genetic factors of HbA1c level in T1D patients after the first year of T1D, to exclude the honeymoon period. A total of 1974 articles published since January 2011 were identified and 78 were finally included in the analysis of non-genetic predictors. For genetic factors, a total of 277 articles were identified and 14 were included. The most significantly associated factors with HbA1c level are demographic (age, ethnicity, and socioeconomic status), personal (family characteristics, parental care, psychological traits...) and features related to T1D (duration of T1D, adherence to treatment …). Only a few studies have searched for genetic factors influencing HbA1c level, most of which focused on candidate genes using classical genetic statistical methods, with generally limited power and incomplete adjustment for confounding factors and multiple testing. Our review shows the complexity of explaining HbA1c level variations, which involves numerous correlated predictors. Overall, our review underlines the lack of studies investigating jointly genetic and non-genetic factors and their interactions to better understand factors influencing glycaemic control for T1D patients.
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http://dx.doi.org/10.1002/dmrr.3051DOI Listing
November 2018

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

Eur J Endocrinol 2018 Sep 4;179(3):181-190. Epub 2018 Jul 4.

Pediatric Endocrinology Department, CHU Robert Debré, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris and Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Objective: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development.

Methods: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.

Results: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% ( = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels).

Conclusion: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.
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http://dx.doi.org/10.1530/EJE-18-0309DOI Listing
September 2018

Serum GH concentration must now be expressed in mass units in France like in the rest of the world.

Ann Biol Clin (Paris) 2018 Apr;76(2):133-134

Service des explorations fonctionnelles, Hôpital Necker-Enfants malades, Assistance Publique des Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1684/abc.2018.1322DOI Listing
April 2018

The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones.

J Biol Chem 2018 04 14;293(14):5134-5149. Epub 2018 Feb 14.

From the Department of Biology, Penn State University, University Park, Pennsylvania 16802,

Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic β cells. As PERK is generally known as a translational regulator of the unfolded protein response (UPR), the underlying cause of these β cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER. Using high-resolution imaging and standard protein fractionation and immunological methods we have examined the PERK-dependent phenotype more closely. We found that whereas proinsulin aggregation requires new protein synthesis, global protein and proinsulin synthesis are down-regulated in PERK-inhibited cells, strongly arguing against proinsulin overproduction being the root cause of their aberrant ER phenotype. Furthermore, we show that PERK regulates proinsulin proteostasis by modulating ER chaperones, including BiP and ERp72. Transgenic overexpression of BiP and BiP knockdown (KD) both promoted proinsulin aggregation, whereas ERp72 overexpression and knockdown rescued it. These findings underscore the importance of ER chaperones working in concert to achieve control of insulin production and identify a role for PERK in maintaining a functional balance among these chaperones.
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http://dx.doi.org/10.1074/jbc.M117.813790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892574PMC
April 2018

Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort.

Clin Chim Acta 2018 Mar 28;478:162-165. Epub 2017 Dec 28.

Immunology Department, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France. Electronic address:

Aim Of The Study: Evaluate the added value of screening anti-ZnT8 antibodies (ZnT8A) in addition to the classical anti-GAD (GADA) and anti-IA-2 (IA-2A) antibodies for the diagnosis of type-1 diabetes (T1D) within a large cohort of both children and adults.

Materials And Methods: Retrospective 2-year study including 516 patients (215 children, 301 adults) who had blood tests at diabetes onset and/or for diabetes classification. ZnT8A, GADA, and IA-2A were analyzed in all samples.

Results: Among those individuals included, 142 (28%) were ZnT8A-positive. A total of 228/516 suffered from T1D, of whom 110 (48%) were ZnT8A-positive and 166 (73%) GADA and/or IA-2A positive. When adding ZnT8A to GADA/IA-2A, 184 (81%) patients were positive for ≥1 Ab. Regarding the 122 patients at T1D onset, 75 (61%) were positive for ZnT8A and the proportion of patients with T1D with ≥1 Ab reached 89%. The highest prevalence of ZnT8A was observed in children aged 6-10years. Fourteen of the 124 patients positive for ZnT8A with a known clinical diagnosis suffered from a disease other than T1D.

Conclusions: ZnT8A should be included in routine evaluation at diabetes onset and is a valuable biological marker to classify newly-diagnosed diabetics. The predictive value in our high-risk subjects has to be confirmed.
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http://dx.doi.org/10.1016/j.cca.2017.12.043DOI Listing
March 2018

Triple-A syndrome: a wide spectrum of adrenal dysfunction.

Eur J Endocrinol 2018 Mar 13;178(3):199-207. Epub 2017 Dec 13.

Univ LyonUniversité Claude Bernard Lyon 1, Lyon, France.

Objective: Triple-A or Allgrove syndrome is an autosomal recessive disorder due to mutations in the gene, which encodes a nucleoporin named ALADIN. It is characterized by a classical clinical triad: alacrima, achalasia and adrenal insufficiency, the canonic symptoms that are associated with progressive peripheral neuropathy. Only a few cohorts have been reported. The objective of the present study was to characterize the various spectra of adrenal function in Triple-A patients.

Methods: A retrospective clinical and biological monitoring of 14 patients (10 families) was done in a single multidisciplinary French center. All had gene sequenced and adrenal function evaluation.

Results: Nine different mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser). Regarding adrenal function, defects of the zona fasciculata and reticularis were demonstrated by increased basal ACTH levels and low DHEAS levels in all cases regardless of the degree of glucocorticoid deficiency. In contrast, mineralocorticoid function was always conserved: i.e., normal plasma renin level associated with normal aldosterone level. The main prognostic feature was exacerbation of neuropathy and cognitive disorders.

Conclusions: These data suggest that, in Triple-A patients, adrenal function can be deficient, insufficient or compensated. In our cohort after the first decade of life, there does not appear to be any degradation of adrenal function over time. However, patients with compensated adrenal function should be informed and educated to manage a glucocorticoid replacement therapy in case of stressful conditions, with no need for systematic long-term treatment.
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http://dx.doi.org/10.1530/EJE-17-0642DOI Listing
March 2018

Serum GH concentrations must now be expressed in mass units in France…as in the rest of the world.

Ann Endocrinol (Paris) 2017 Dec;78(6):488-489

Service des explorations fonctionnelles, hôpital Necker-Enfants malades, Assistance publique des hôpitaux de Paris (AP-HP), 149, rue de Sèvres, 75015 Paris, France.

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http://dx.doi.org/10.1016/j.ando.2017.11.002DOI Listing
December 2017

Juvenile-Onset Diabetes and Congenital Cataract: "Double-Gene" Mutations Mimicking a Syndromic Diabetes Presentation.

Genes (Basel) 2017 Nov 7;8(11). Epub 2017 Nov 7.

INSERM UMR-S 958, Faculté de Médecine Paris Diderot, University Paris 7 Denis-Diderot, Sorbonne Paris Cité, Paris 75010, France.

Monogenic forms of diabetes may account for 1-5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in , a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the mutation, and both the mother and one unaffected sibling were heterozygous for the mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of mutations is well documented, but this is the first report of an incomplete penetrance of a mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity.
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http://dx.doi.org/10.3390/genes8110309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704222PMC
November 2017

Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance.

J Autoimmun 2017 May 9;79:84-90. Epub 2017 Feb 9.

LASER Europe Ltd, London, 66 Chiltern St, London W1U 4JT, United Kingdom; Department of Epidemiology, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK.

Background: Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization.

Objectives: To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France.

Methods: Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11-25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008-2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations.

Results: With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41-0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results.

Conclusion: Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.
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http://dx.doi.org/10.1016/j.jaut.2017.01.005DOI Listing
May 2017

dUTPase () Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.

Diabetes 2017 04 10;66(4):1086-1096. Epub 2017 Jan 10.

INSERM UMRS 958, Faculté de Médecine Paris Diderot, Université Paris Diderot-Paris 7, Université Sorbonne Paris Cité, Paris, France

We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase () gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.
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http://dx.doi.org/10.2337/db16-0839DOI Listing
April 2017

Growth curves for congenital adrenal hyperplasia from a national retrospective cohort.

J Pediatr Endocrinol Metab 2016 Dec;29(12):1379-1388

Background: In congenital adrenal hyperplasia (CAH), adjusting hydrocortisone dose during childhood avoids reduced adult height. However, there are currently no CAH-specific charts to monitor growth during treatment. Our objective was to elaborate growth reference charts and bone maturation data for CAH patients.

Methods: We conducted a retrospective observational cohort study, in 34 French CAH centers. Patients were 496 children born 1970-1991 with genetically proven 21-hydroxylase deficiency. Their growth and bone maturation data were collected until age 18 together with adult height, puberty onset, parental height, and treatment. The mean (SD) heights were modeled from birth to adulthood. The median±1 SD and ±2 SDs model-generated curves were compared with the French references. A linear model for bone maturation and a logistic regression model for the probability of short adult height were built.

Results: Growth charts were built by sex for salt wasting (SW) and simple virilizing (SV) children treated before 1 year of age. In girls and boys, growth was close to that of the general French population up to puberty onset. There was almost no pubertal spurt and the mean adult height was shorter than that of the general population in girls (-1.2 SD, 156.7 cm) and boys (-1.0 SD, 168.8 cm). Advanced bone age at 8 years had a strong impact on the risk of short adult height (OR: 4.5 per year advance).

Conclusions: The 8-year bone age is a strong predictor of adult height. It will help monitoring the growth of CAH-affected children.
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http://dx.doi.org/10.1515/jpem-2016-0156DOI Listing
December 2016

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

Authors:
F Balazard S Le Fur S Valtat A J Valleron P Bougnères Dominique Thevenieau Corinne Fourmy Chatel Rachel Desailloud Hélène Bony-Trifunovic Pierre-Henri Ducluzeau Régis Coutant Sophie Caudrelier Armelle Pambou Emmanuelle Dubosclard Florence Joubert Philippe Jan Estelle Marcoux Anne-Marie Bertrand Brigitte Mignot Alfred Penformis Chantal Stuckens Régis Piquemal Pascal Barat Vincent Rigalleau Chantal Stheneur Sylviane Fournier Véronique Kerlan Chantal Metz Anne Fargeot-Espaliat Yves Reznic Frédérique Olivier Iva Gueorguieva Arnaud Monier Catherine Radet Vincent Gajdos Daniel Terral Christine Vervel Djamel Bendifallah Candace Ben Signor Daniel Dervaux Abdelkader Benmahammed Guy-André Loeuille Françoise Popelard Agnès Guillou Pierre-Yves Benhamou Jamil Khoury Jean-Pierre Brossier Joachim Bassil Sylvaine Clavel Bernard Le Luyer Pierre Bougnères Françoise Labay Isabelle Guemas Jacques Weill Jean-Pierre Cappoen Sylvie Nadalon Anne Lienhardt-Roussie Anne Paoli Claudie Kerouedan Edwige Yollin Marc Nicolino Gilbert Simonin Jacques Cohen Catherine Atlan Agnès Tamboura Hervé Dubourg Marie-Laure Pignol Philippe Talon Stéphanie Jellimann Lucy Chaillous Sabine Baron Marie-Noëlle Bortoluzzi Elisabeth Baechler Randa Salet Ariane Zelinsky-Gurung Fabienne Dallavale Etienne Larger Marie Laloi-Michelin Jean-François Gautier Bénédicte Guérin Laure Oilleau Laetitia Pantalone Céline Lukas Isabelle Guilhem Marc De Kerdanet Marie-Claire Wielickzo Mélanie Priou-Guesdon Odile Richard François Kurtz Norbert Laisney Déborah Ancelle Guilhem Parlier Catherine Boniface Dominique Paris Bockel Denis Dufillot Berthe Razafimahefa Pierre Gourdy Pierre Lecomte Myriam Pepin-Donat Marie-Emmanuelle Combes-Moukhovsky Brigitte Zymmermann Marina Raoulx Anne Gourdin Et Catherine Dumont

BMC Public Health 2016 Sep 29;16(1):1021. Epub 2016 Sep 29.

INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.

Background: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D.

Methods: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods.

Results: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age.

Conclusions: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas.

Trial Registration: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.
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http://dx.doi.org/10.1186/s12889-016-3690-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041527PMC
September 2016

miRNA-375 a Sensor of Glucotoxicity Is Altered in the Serum of Children with Newly Diagnosed Type 1 Diabetes.

J Diabetes Res 2016 24;2016:1869082. Epub 2016 May 24.

CarMeN Laboratory (INSERM 1060, INRA 1362, INSA), Lyon-Sud Faculty of Medicine, University of Lyon, Chemin du Grand Revoyet, 69600 Oullins, France.

Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array. Results. The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies. Conclusion. Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.
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http://dx.doi.org/10.1155/2016/1869082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895032PMC
May 2017

[WHAT IS THE RISK FOR CHILDHOOD OBESITY?].

Rev Prat 2015 Dec;65(10):1275-7

The complications of obesity may be observed during childhood. They include multiple and varied anomalies that are found in all major organ systems. These abnormalities occur in the more or less long term. In this context, the question of the impact of early development of obesity on overall health status and mortality is asked. The most frequent comorbidities are described and the different clinical and para-clinical indicators that allow to detect them.
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December 2015

Growth patterns of patients with Noonan syndrome: correlation with age and genotype.

Eur J Endocrinol 2016 May 22;174(5):641-50. Epub 2016 Feb 22.

EndocrineBone Diseases, and Genetics Unit, Children's Hospital, Toulouse University Hospital, Toulouse, France INSERM UMR 1043Centre of Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France

Background: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.

Objective: The goal of this study was to compare growth parameters according to genotype in patients with NS.

Subjects And Methods: The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.

Results: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): -1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being -2.1 ± 1.3 at 2 years, and -2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated.

Conclusion: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.
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http://dx.doi.org/10.1530/EJE-15-0922DOI Listing
May 2016

Management of adolescents with very poorly controlled type 1 diabetes by nurses: a parallel group randomized controlled trial.

Trials 2015 Sep 8;16:399. Epub 2015 Sep 8.

Endocrinologie, Diabétologie, Nutrition Pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, F-69677, Bron, France.

Backgrounds: Fluctuation in glycemia due to hormonal changes, growth periods, physical activity, and emotions make diabetes management difficult during adolescence. Our objective was to show that a close control of patients' self-management of diabetes by nurse-counseling could probably improve metabolic control in adolescents with type 1 diabetes.

Methods: We designed a multicenter, randomized controlled, parallel group, clinical trial. Seventy seven adolescents aged 12-17 years with A1C >8% were assigned to either an intervention group (pediatrician visit every 3 months + nurse visit and phone calls) or to the control group (pediatrician visit every 3 months). The primary outcome was the evolution of the rate of A1C during the 12 months of follow-up. Secondary outcomes include patient's acceptance of the disease (evaluated by visual analog scale), the number of hypoglycemic or ketoacidosis episodes requiring hospitalization, and evaluation of A1C rate over time in each group.

Results: Seventy-seven patients were enrolled by 10 clinical centers. Seventy (89.6%) completed the study, the evolution of A1C and participants satisfaction over the follow-up period was not significantly influenced by the nurse intervention.

Conclusion: Nurse-led intervention to improve A1C did not show a significant benefit in adolescents with type 1 diabetes because of lack of power. Only psychological management and continuous glucose monitoring have shown, so far, a slight but significant benefit on A1C. We did not show improvements in A1C control in teenagers by nurse-led intervention.

Trial Registration: Clinical Trials.gov registration number: NCT00308256, 28 March 2006.
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http://dx.doi.org/10.1186/s13063-015-0923-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563922PMC
September 2015

Early Neurodegeneration in the Brain of a Child Without Functional PKR-like Endoplasmic Reticulum Kinase.

J Neuropathol Exp Neurol 2015 Aug;74(8):850-7

From the Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE) Munich (JB, CK, GUH); Department of Neurology, Technische Universität München (JB, CK, GUH); Department of Psychiatry and Psychotherapy (TA) and Center for Neuropathology and Prion Research (TA), Ludwig Maximilians Universität, Munich, Germany; and Department of Pathology and Neuropathology, Groupement Hospitalier Est, Bron (AV), and Division of Pediatric Endocrinology, Lyon University Pediatric Hospital, Lyon (MN), France.

We report the first detailed examination of the brain of a patient with Wolcott-Rallison syndrome. Wolcott-Rallison syndrome is an extremely rare clinical manifestation of a lack of protein kinase R-like endoplasmic reticulum kinase (PERK) function caused by mutations in the PERK gene EIF2AK3. Protein kinase R-like endoplasmic reticulum kinase is thought to play a significant pathogenetic role in several neurodegenerative diseases, including Alzheimer disease, other tauopathies, and Parkinson disease. The brain of a male patient aged 4 years 7 months showed pathologic and immunohistochemical evidence that the absence of PERK for several years is sufficient to induce early changes reminiscent of various neurodegenerative conditions. These include neurofibrillary tangles (as in progressive supranuclear palsy), FUS-immunopositive and p62-immunopositive neurons, and reactive glial changes. We also detected an increased amount of p62-positive puncta coimmunostaining for LC3 and ubiquitin, suggesting changes in autophagic flux. Studying a human brain with absent PERK function presents the opportunity to assess the long-term consequences of nonfunctioning of PERK in the presence of all of the compensatory mechanisms that are normally active in a living human, thereby confirming the importance of PERK for autophagy in the brain and for neurodegeneration.
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http://dx.doi.org/10.1097/NEN.0000000000000224DOI Listing
August 2015

A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.

Diabetes 2015 Nov 9;64(11):3951-62. Epub 2015 Jul 9.

INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2α dephosphorylation and results in β-cell apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.
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http://dx.doi.org/10.2337/db15-0477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713904PMC
November 2015

Seven novel deleterious LEPR mutations found in early-onset obesity: a ΔExon6-8 shared by subjects from Reunion Island, France, suggests a founder effect.

J Clin Endocrinol Metab 2015 May 9;100(5):E757-66. Epub 2015 Mar 9.

Institute of Cardiometabolism and Nutrition (H.H., R.A., J.-M.L., P.T., C.P., B.D., K.C.), Pitié-Salpêtrière Hospital, Nutrition Department, Paris F-75013, France; Sorbonne Universities (H.H., J.L.B., J.-M.L., C.P., K.C.), University Pierre et Marie Curie-Paris 6, Paris F-75006, France; INSERM (H.H., R.A., P.T., C.P., B.D., K.C.), Unité Mixte de Recherche (UMR)_S U1166, Nutriomics, Paris F-75013, France; Groupement des Hôpitaux de l'Institut Catholique de Lille (H.H.), St-Vincent de Paul Hospital, Department of Pediatrics, Lille F-59000, France; Assistance Publique-Hôpitaux de Paris (J.L.B., D.P., J.-M.L.), Pitié-Salpêtrière Hospital, Department of Biochemical Endocrinology and Oncology, Nutrigénétique, Paris F-75013, France; INSERM (J.L.B.), UMR_S U1149, Université François-Rabelais de Médecine Paris Diderot, Paris F-75018, France; Félix-Guyon-Bellepierre Hospital (P.P.K.), Department of Pediatrics, St-Denis F-97405, Reunion, France; St François d'Assise Association (E.J.), Department of Pediatric Nutrition, St-Denis F-97405, Reunion, France; Assistance Publique Hôpitaux de Paris (M.-L.F.), Bicêtre Hospital, Department of Pediatric Endocrinology and Diabetology, Kremlin-Bicêtre F-94270, France; INSERM (J.-M.L.), Integrative Biology of Atherosclerosis, UMR_S U1166, Paris F-75013, France; Mother and Child Hospital (M.N.), Department of Pediatric Endocrinology, Lyon F-69000, France; Robert Debré Hospital (A.V.), Department of Endocrinology, Reims F-51100, France; Lyon-Sud Hospital (M.L.), Department of Endocrinology, Diabetology, and Nutrition, Lyon F-69000, France; Assistance Publique-Hôpitaux de Paris (S.L.), Functional Explorations, Louis Mourier Hospital, Obesity Center, Colombes F-92700, France; and Assistance Publique-Hôpitaux de Paris (P.T., B.D.), Department of Pediatric Nutrition and Gastroenterology, Armand-Trousseau Hospital, Paris F-75571, France.

Context: Infrequent mutations have been reported in the leptin receptor (LEPR) gene in humans with morbid obesity and endocrine disorders. However LEPR mutations are rarely examined in large populations from different ethnicities in a given country.

Objective: We estimated the prevalence of LEPR mutations in French patients with severe obesity and evaluated mutated patients' phenotype.

Design And Patients: We sequenced the LEPR gene in 535 morbidly obese French participants. We conducted clinical investigations to determine whether individuals with a novel shared mutation display particular characteristics relative to obesity history, body composition, hormonal functions, and the outcome of bariatric surgery.

Results: We identified 12 patients with a novel LEPR mutation (p.C604G, p.L786P, p.H800_N831del, p.Y422H, p.T711NfsX18, p.535-1G>A, p.P166CfsX7). Six unrelated subjects were carriers of the p.P166CfsX7 mutation leading to deletion overlapping exons 6 to 8. All subjects originated from Reunion Island (France). Their clinical features (severe early-onset obesity, food impulsivity, and hypogonadotropic hypogonadism) did not differ from other new LEPR mutation carriers. Results concerning weight loss surgery were inconsistent in homozygous LEPR mutation carriers. Heterozygous LEPR mutation carriers exhibited variable severity of obesity and no endocrine abnormality.

Conclusion: Among seven newly discovered LEPR mutations in this French obese population, we identified a LEPR frameshift mutation shared by six subjects from Reunion Island. This observation suggests a founder effect in this Indian Ocean island with high prevalence of obesity and supports a recommendation for systematic screening for this mutation in morbidly obese subjects in this population.
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http://dx.doi.org/10.1210/jc.2015-1036DOI Listing
May 2015

Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients.

J Clin Endocrinol Metab 2015 Mar 22;100(3):1177-86. Epub 2014 Dec 22.

Service d'Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., T.B., P.K., J.Y., P.C.), and Service de Génétique Moléculaire, Pharmacogénétique, et Hormonologie (J.B., A.G.-M.), and Service d'Endocrinologie Pédiatrique and Centre de Référence des Maladies Rares du Métabolisme Phospho-Calcique, (A.L.), Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, F-94275, France; Service d'Endocrinologie (D.A., B.D.) and Service de Pédiatrie (P.-F.S.), Centre Hospitalier Universitaire de Reims, Hôpital Robert Debré, Reims, F-51092, France; Faculté de Médecine (G.R., M.N., F.B.-C.), Université de Lyon, Lyon 1, Lyon-Est, Lyon F-69372 France; Fédération d'Endocrinologie (G.R., F.B.-C.) and Service d'Endocrinologie Pédiatrique (M.N.), Hôpital Femme-Mère-Enfant, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, F-69003, France; Institut National de la Santé et de la Recherche Médicale Unité 1028 (G.R.), Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5292, Lyon Neuroscience Research Center, Service de Neurooncology-Neuroinflammation, and INSERM Unité 1052 (F.B.-C.), Unité Mixte de Recherche Centre National de la Recherche Scientifique Unité 5286, Centre de Recherche en Cancérologie de Lyon, Equipe Tumeurs Endocrines, Lyon, F-69000, France; Unité Mixte de Recherche Scientifique Unité 693 (P.K., J.B., A.M., A.L., J.Y., P.C.), Faculté de Médecine Paris-Sud, Université Paris-Sud 11, Le Kremlin-Bicêtre F-94276, France; INSERM Unité 986 (A.L.) and INSERM Unité 693 (P.K., J.B., A.M., J.Y., P.C.), Le Kremlin-Bicêtre F-94276, France.

Background: Pituitary adenomas are rare in children and adolescents. The response of macroprolactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in adults.

Objective: We retrospectively analyzed data on a large cohort of young patients with macroprolactinomas.

Patients And Methods: Patients aged younger than 20 years at macroprolactinoma diagnosis and seen in three tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the patients' status at their last visit, after a mean (±SD) follow-up of 8.2 ± 5.8 years, was assessed.

Results: The cohort comprised 77 patients (26 males, 51 females). Mean age at diagnosis was 16.1 ± 2.5 years (range, 4.5-20 y). In both sexes, the most frequent revealing symptom was a pubertal disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal prolactin (PRL) levels and maximal tumor diameter were significantly higher in boys than in girls (7168 ng/mL, 202-40 168 vs 1433 ng/mL, 115-20 000, P = .002; and 33 ± 14 mm, 15-64 vs 19 ± 9 mm; 10-50, P < .001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP or MEN1 was found in 14% of the patients. Factors associated with resistance to DA were young age, higher PRL levels, larger volume, and the presence of a MEN1 (but not an AIP) mutation.

Conclusion: Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and during adolescence. Like adults, young patients are very sensitive to DA, which should therefore be considered the first-line treatment. DA resistance is associated with a higher PRL level and larger tumor size, both parameters being closely linked together. About 14% of these young patients have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance.
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http://dx.doi.org/10.1210/jc.2014-3670DOI Listing
March 2015

Microscopic and ultrastructural features in Wolcott-Rallison syndrome, a permanent neonatal diabetes mellitus: about two autopsy cases.

Pediatr Diabetes 2015 Nov 18;16(7):510-20. Epub 2014 Aug 18.

Department of Endocrinology, Children and Mother's Hospital, Groupement Hospitalier Est, CHU de Lyon-Bron, France.

Background: Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple bone dysplasia, hepatic dysfunction, and growth retardation. All clinical manifestations result from gene mutations encoding pancreatic endoplasmic reticulum eIF2 α kinase (PERK), an endoplasmic reticulum transmembrane protein that plays a role in the unfolded protein response. Histological and ultrastructural lesions of bone and pancreas have been described in animal models and WRS patients. However, histological and ultrastructural findings of other organs, especially of the liver, are lacking.

Methods: Autopsy specimens from two pediatric patients with WRS were analyzed. An immunohistochemical study was performed on the pancreas. An ultrastructural study was realized from samples of liver, pancreas, kidney, and myocardium. Our findings were compared with those of the literature and correlated with the molecular data.

Results: Hepatocytes and pancreatic exocrine cells exhibited very peculiar features of necrosis suggestive of secondary changes because of endoplasmic reticulum overload. Steatosis occurred in renal tubular cells, hepatocytes, and myocardial fibers. Abnormal mitochondria were noted in renal and myocardial fibers. Pancreas islets were characterized by a marked reduction in the number of insulin-secreting β cells.

Conclusions: The histological and ultrastructural features that occur in WRS are directly or indirectly linked to endoplasmic reticulum (ER) dysfunction and can explain the peculiar phenotype of this syndrome.
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http://dx.doi.org/10.1111/pedi.12201DOI Listing
November 2015

Uncommon cause of large paravertebral calcification in a child.

J Pediatr 2013 Apr 16;162(4):881. Epub 2012 Nov 16.

Department of Pediatric Endocrinology and Metabolism, Hopital Femme-Mere-Enfant, Lyon/Bron, France.

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http://dx.doi.org/10.1016/j.jpeds.2012.10.016DOI Listing
April 2013

Fetal ovarian cysts: an early manifestation of McCune-Albright syndrome?

Prenat Diagn 2012 Sep 13;32(9):859-63. Epub 2012 Jun 13.

Unité d'Endocrinologie-Gynécologie Pédiatriques, Service de Pédiatrie, Hôpital Arnaud-de-Villeneuve, CHU Montpellier et Université Montpellier 1, Montpellier, France.

Objective: Beyond the classic triad of peripheral precocious puberty, café-au-lait skin pigmentation and polyostotic fibrous dysplasia, partial presentation McCune-Albright syndrome (MAS) has been reported, including the association of isolated recurrent ovarian cysts in early infancy. The aims of this study were to determine whether isolated voluminous fetal unilateral ovarian cysts (diameter > 4 cm) may be associated with a Gsα activating mutation, suggestive of MAS.

Design: We followed five female fetuses presenting with voluminous unilateral ovarian cysts by ultrasonography until delivery. At birth, all patients underwent percutaneous cyst aspiration and two patients later underwent ovariectomy. A sensitive PCR-based method was used to analyze the Gsα activating mutation in DNA obtained from ovarian cystic fluids or tissue.

Results: Among the five cases, one Gsα mutation (R201C) was identified in the ovarian tissue.

Conclusions: We demonstrate for the first time that voluminous fetal unilateral ovarian cysts may be suggestive of MAS. Systematic search for the Gsα mutation should be performed in all newborns with voluminous fetal unilateral ovarian cysts requiring percutaneous cyst aspiration, because early diagnosis of MAS prevents unnecessary oophorectomy to eliminate questions of malignancy and imposes long-term clinical, biological, and imaging follow-up to detect other early manifestations of MAS.
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http://dx.doi.org/10.1002/pd.3921DOI Listing
September 2012