Publications by authors named "Graziella Pinto"

36 Publications

Paradoxical low severity of COVID-19 in Prader-Willi syndrome: data from a French survey on 647 patients.

Orphanet J Rare Dis 2021 07 21;16(1):325. Epub 2021 Jul 21.

Assistance Publique-Hôpitaux de Paris, Centre de référence Maladies Rares (PRADORT, Syndrome de Prader-Willi et autres formes rares d'obésité avec troubles du comportement alimentaire), Hôpital Marin d'Hendaye, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), Hendaye, France.

Background: Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-CoV-2 infection in children and adults with PWS. From November 2020 to January 2021, we performed a detailed medical survey on 342 adults and 305 children with PWS followed in the French reference center.

Results: We obtained responses from 288 adults (84%) and 239 children (78%). From March 2020 to January 2021, 38 adults (13.2%) and 13 children (5.4%) with PWS had SARS-CoV-2 infection. Mean age of adults was 34.1 ± 11.9 years and mean body mass index was 40.6 ± 12.7 kg/m; 82% had obesity and 37% had diabetes. Only 3 children (23%) had obesity and none had diabetes. Similar to the general population, the most frequent symptoms of COVID-19 were asthenia, fever, cough, headache and shortness of breath. All patients had a favorable outcome.

Conclusion: PWS itself is not a risk factor for severe COVID-19 in children and adults. On the contrary, evolution of SARS-CoV-2 infection in adults with PWS seems more favorable than expected, given their comorbidities.
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http://dx.doi.org/10.1186/s13023-021-01949-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294211PMC
July 2021

Is ghrelin a biomarker of early-onset scoliosis in children with Prader-Willi syndrome?

Orphanet J Rare Dis 2021 07 8;16(1):305. Epub 2021 Jul 8.

Endocrinology, Obesity, Bone Diseases, Genetics and Gynecology Unit, Children's Hospital, University Hospital Center of Toulouse, Toulouse, France.

Background: Adolescents with idiopathic scoliosis display high ghrelin levels. As hyperghrelinemia is found in patients with PWS and early-onset scoliosis (EOS) is highly prevalent in these patients, our aims were to explore (1) whether ghrelin levels differ between those with and without EOS and correlate with scoliosis severity, and (2) whether ghrelin levels in the first year of life are associated with the later development of EOS.

Methods: We used a case control study design for the first question and a longitudinal design for the second. Patients with PWS having plasma ghrelin measurements recorded between 2013 and 2018 in our database were selected and 30 children < 10 years old with EOS and 30 age- and BMI-matched controls without EOS were included. The Cobb angle at diagnosis was recorded. In addition, 37 infants with a ghrelin measurement in the first year of life were followed until 4 years of age and assessed for EOS. Total ghrelin (TG), acylated (AG) and unacylated ghrelin (UAG), and the AG/UAG ratio were analyzed.

Results: EOS children had an AG/UAG ratio statistically significantly lower than controls. The Cobb angle was positively correlated with TG and UAG. TG and AG in the first year of life were higher in infants who later develop EOS without reaching a statistically significant difference.

Conclusions: Our results suggest that ghrelin may play a role in the pathophysiology of EOS in PWS. Higher ghrelinemia in the first year of life required careful follow-up for EOS.
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http://dx.doi.org/10.1186/s13023-021-01930-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265004PMC
July 2021

Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2021 Mar 12;19(1):27. Epub 2021 Mar 12.

Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants-Malades University Hospital, Assistance Publique Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.

Background: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.

Case Report: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.

Conclusion: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
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http://dx.doi.org/10.1186/s12969-021-00523-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953742PMC
March 2021

High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis.

Front Endocrinol (Lausanne) 2020 22;11:545339. Epub 2021 Feb 22.

INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objective: To 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 Design: We 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 prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.

Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved , followed by , , and 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.

Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. 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.
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http://dx.doi.org/10.3389/fendo.2020.545339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937947PMC
May 2021

Transition of young adults with endocrine and metabolic diseases: the 'TRANSEND' cohort.

Endocr Connect 2021 Jan;10(1):21-28

AP-HP. Sorbonne Université, Hôpital Universitaire Pitié Salpêtrière-Charles Foix, Service d'Endocrinologie et Médecine de la Reproduction, Centre de Maladies Endocriniennes Rares de la Croissance et du Développement, Centre de Pathologies Gynécologiques Rares, Paris, France.

Objective: The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach.

Design: A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016.

Methods: Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector).

Results: The cohort included 500 patients, with malignant brain tumour (n = 56 (11%)), obesity (n = 55 (11%)), type 1 diabetes (n = 54 (11%)), or other disease (n = 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor's advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity.

Conclusions: Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.
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http://dx.doi.org/10.1530/EC-20-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923139PMC
January 2021

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

Pediatr Dermatol 2020 May 10;37(3):541-544. Epub 2020 Mar 10.

Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), APHP, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.
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http://dx.doi.org/10.1111/pde.14139DOI Listing
May 2020

Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study.

Transl Psychiatry 2019 11 4;9(1):274. Epub 2019 Nov 4.

Service Universitaire de Psychiatrie de l'Enfant et de l'Adolescent, CHU de Nantes, Nantes, France.

Prader-Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12-45 years) had genetically confirmed PWS and severe irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50-200 mg/day) for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose-effect relationship. DHK scores were also significantly associated with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had therefore a significant effect on eating disorders, with a dose-effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic option within the global care of obesity in individuals with PWS.
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http://dx.doi.org/10.1038/s41398-019-0597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828670PMC
November 2019

Causes of death in Prader-Willi syndrome: lessons from 11 years' experience of a national reference center.

Orphanet J Rare Dis 2019 11 4;14(1):238. Epub 2019 Nov 4.

Endocrinology, Obesity, Bone Diseases, Genetics and Gynecology Unit, Children's Hospital, University Hospital Center of Toulouse, Toulouse, France.

Background: In the last 20 years, substantial improvements have been made in the diagnosis, treatment and management of patients with Prader-Willi syndrome (PWS). Few data on causes of death are available since those improvements were made. Our study assessed the causes of death among French patients with PWS over the first 11 years of experience of the nationwide French Reference Center for PWS (FRC-PWS).

Methods: Our study relied on two sources of mortality information at national level between 2004 and 2014: The French Epidemiological Centre for the Medical Causes of Death (CépiDc) Registry and the FRC-PWS database. Causes of death were classified into seven categories: respiratory, cardiovascular, gastrointestinal, severe infection, sudden death, other causes, and unknown. Descriptive statistics were calculated separately for children (< 18 years-old) and adults (≥18 years-old).

Results: One hundred and four deaths were identified in France from 2004 to 2014. The median age at death was 30 years, ranging from less than 1 month to 58 years. Seventeen deaths occurred in patients under 18 years, with 70% of them in children under 2 years. Respiratory causes accounted for more than 50% of the deaths in patients with PWS in both children and adults. Both cause and age of death did not significantly differ according to gender or genetic subtype.

Conclusions: Patients with PWS die prematurely due to a respiratory cause in most cases at all ages. In those adult patients with data on obesity, 98% were reported to be obese.
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http://dx.doi.org/10.1186/s13023-019-1214-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829836PMC
November 2019

Sleep-disordered breathing in children with pycnodysostosis.

Am J Med Genet A 2020 01 3;182(1):122-129. Epub 2019 Nov 3.

ASV Santé, Gennevilliers, France.

Upper airway obstruction is a common feature in pycnodysostosis and may cause obstructive sleep apnea (OSA). The aim of our study was to analyze sleep-disordered breathing and respiratory management in children with pycnodysostosis. A retrospective review of the clinical charts and sleep studies of 10 consecutive children (three girls and seven boys) with pycnodysostosis seen over a time period of 10 years was performed. Six patients had severe OSA and/or nocturnal hypoventilation and were started on continuous positive airway pressure (CPAP) as a first treatment at a median age of 3.4 ± 2.6 years, because of the lack of indication of any surgical treatment. Three patients could be weaned after several years from CPAP after spontaneous improvement (two patients) or multiple upper airway surgeries (one patient). Three patients had upper airway surgery prior to their first sleep study with two patients still needing CPAP during their follow-up. Only one patient never developed OSA. Patients with pycnodysostosis are at a high risk of severe OSA, underlying the importance of a systematic screening for sleep-disordered breathing. Multidisciplinary care is mandatory because of the multilevel airway obstruction. CPAP is very effective and well accepted for treating OSA.
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http://dx.doi.org/10.1002/ajmg.a.61393DOI Listing
January 2020

Improved General and Height-Specific Quality of Life in Children With Short Stature After 1 Year on Growth Hormone.

J Clin Endocrinol Metab 2019 06;104(6):2103-2111

Pediatric Endocrinology, Diabetology and Gynecology Department, Hôpital Universitaire Necker-Enfants Malades [Assistance Publique Hôpitaux de Paris (AP-HP)], Paris, France.

Objective: Short stature in children and adolescents may lead to social and emotional stress, with negative effects on quality of life (QoL). GH treatment may improve QoL through height normalization. Our objective here was to evaluate general and height-specific QoL after 1 year of GH treatment.

Design: Prospective, single-center, observational cohort study.

Methods: Children ≥ 4 years of age starting GH at our center from 2012 to 2015 to treat short stature were studied. Patients with serious diseases, syndromic short stature, or developmental delay were excluded. At treatment initiation and 1 year later, patients and their parents completed the general PedsQL 4.0 and height-specific Quality of Life in Short Stature Youth (QoLiSSY) questionnaires. Correlations between self-report and parent-report scores and between height gain and QoL improvements were assessed based on Pearson correlation coefficients.

Results: Seventy-four children (42 boys, 32 girls), median age (± SD), 10.2 ± 3.0 years (range, 4.1 to 16.6 years), were included. The self-report PedsQL indicated significant improvements in emotional (P = 0.02) and social (P = 0.03) QoL. As assessed by the QoLiSSY, children reported improvement of social QoL (+0.2 SD; P = 0.04), and parents reported improvement of children's physical (+0.1 SD; P < 0.0001), emotional (+0.3 SD; P < 0.0001), and social (+0.3 SD; P < 0.0001) QoL. Height SD score (SDS) gains showed moderate positive correlations with QoLISSY self-report score gains (R = 0.53, R2 = 0.28; P < 0.001) and QoLISSY parent-report gains (R = 0.60, R2 = 0.41; P < 0.00001).

Conclusions: After 1 year of GH treatment, children had significant gains in emotional and social QoL, as assessed by a general self-report questionnaire and height-specific parent-report questionnaire.
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http://dx.doi.org/10.1210/jc.2018-02523DOI Listing
June 2019

Arterial Spin Labeling and Central Precocious Puberty.

Clin Neuroradiol 2020 Mar 5;30(1):137-144. Epub 2018 Nov 5.

Department of Pediatric Radiology, Hôpital Necker Enfants Malades, AP-HP, 149 rue de sèvres, 75015, Paris, France.

Purpose: To evaluate a non-invasive method to assess the progressivity of idiopathic central precocious puberty (CPP) by quantifying perfusion of the pituitary stalk with arterial spin labeling (ASL) and using the gonadotropin-releasing hormone (GnRH) test as a reference test to define progressive CPP.

Methods: In a single center retrospective study, 52 consecutive patients, observed between October 2015 and April 2017 and referred with early signs of puberty, were evaluated using the GnRH test and cerebral magnetic resonance imaging (MRI). Patients with peripheral or non-idiopathic puberty were excluded. The distribution of perfusion values between patients with progressive and non-progressive CPP was compared using a nonparametric Mann-Whitney U‑test.

Results: In this study 35 patients were included and 29 had progressive CPP. These patients displayed significantly higher cerebral blood flow (CBF) values than the 6 patients with non-progressive CPP (p = 0.006). The median CBF for patients with non-progressive and progressive CPP was 45.25 ml/min/100 g (interquartile range 36.9-54) vs. 65 ml/min/100 g (interquartile range 55.5-74.5), respectively. To determine if the CPP was progressive, the best CBF threshold was 55.5 ml/min/100 g with a sensitivity of 76%, a specificity of 83% and an accuracy of 77%. There were strong significant correlations between CBF and LH peak (r = 0.67, p < 0.001) and between CBF and LH/FSH peaks ratio [r = 0.71, p < 0.001] during the GnRH test.

Conclusion: Arterial spin labelling (ASL) offers a novel tool to assess the progressivity of idiopathic CPP.
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http://dx.doi.org/10.1007/s00062-018-0738-5DOI Listing
March 2020

Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy
.

Horm Res Paediatr 2017 12;87(2):103-110. Epub 2017 Jan 12.

Background: Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis.

Methods: Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone [AMH]), and ultrasound of penis/testes.

Results: In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 ± 4.06 ng/mL [12.15 ± 14.09 nmol/L]), SPL (from 13.8 ± 4.5 to 42.6 ± 5 mm; p < 0.0001), inhibin B (from 94.8 ± 74.9 to 469.4 ± 282.5 pg/mL, p = 0.04), and AMH (from 49.6 ± 30.6 to 142 ± 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm.

Conclusions: Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long-term follow-up is needed to assess the impact, if any, on future fertility and reproduction.
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http://dx.doi.org/10.1159/000454861DOI Listing
June 2017

Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood.

Orphanet J Rare Dis 2017 01 5;12(1). Epub 2017 Jan 5.

Reference Center of Inherited Metabolic Diseases, Imagine Institute, Hospital Necker Enfants Malades, APHP, University Paris Descartes, Paris, France.

Background: Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit yLAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management.

Results: Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16).

Conclusions: As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.
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http://dx.doi.org/10.1186/s13023-016-0550-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217205PMC
January 2017

Central sleep apnea in children: experience at a single center.

Sleep Med 2016 09 31;25:24-28. Epub 2016 Aug 31.

Pediatric Noninvasive Ventilation and Sleep Unit, AP-HP, Hôpital Necker Enfants-Malades, Paris, France; Paris Descartes University, Paris, France; Inserm U955, Team 13, Créteil Université, Paris XII, Créteil, France.

Objective: Central sleep apnea (CSA) syndromes are rare in children and data in children over one year of age are scarce. The aim of the study was to describe the sleep characteristics, underlying disorders, management, and outcome of children with CSA.

Patients/methods: A retrospective chart review of all children >1 year of age, diagnosed with CSA on a laboratory sleep study during a 20-month period, was performed. CSA was defined by a central apnea index (CAI) >5 events/h. The clinical management and the patient's outcome were analyzed.

Results: Eighteen of 441 (4.1%) patients recorded during the study period had CSA. The median CAI, pulse oximetry, and oxygen desaturation index were 13/h (range 6-146), 96% (93-98%), and 18/h (6-98), respectively. Neurosurgical pathologies represented the most common underlying disorders with Arnold-Chiari malformation in four and ganglioglioma in three patients. Other underlying disorders were Prader-Willi syndrome (N = 3), achondroplasia (N = 2), and Down syndrome, with one patient having an achondroplasia and a Down syndrome. The remaining six patients had other genetic diseases. The most common investigation was brain magnetic resonance imaging (MRI). Individualized management with neurosurgery and/or chemotherapy, continuous positive airway pressure (in two patients having associated obstructive events), or noninvasive ventilation resulted in an improvement in CSA and the clinical presentation in 11 patients.

Conclusion: CSA is rare in children >1 year of age. Underlying disorders are dominated by neurosurgical disorders. Individualized management is able to improve CSA and the clinical condition in most patients.
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http://dx.doi.org/10.1016/j.sleep.2016.07.016DOI Listing
September 2016

Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome.

Am J Hum Genet 2016 08 14;99(2):407-13. Epub 2016 Jul 14.

Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, and Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France. Electronic address:

Cardiospondylocarpofacial (CSCF) syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families and ranging in age from 5 to 37 years. MAP3K7 encodes transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), which is involved in the mitogen-activated protein kinase (MAPK)-p38 signaling pathway. MAPK-p38 signaling was markedly altered when expression of non-canonical TGF-β-driven target genes was impaired. These findings support the loss of transcriptional control of the TGF-β-MAPK-p38 pathway in fibroblasts obtained from affected individuals. Surprisingly, although TAK1 is located at the crossroad of inflammation, immunity, and cancer, this study reports MAP3K7 mutations in a developmental disorder affecting mainly cartilage, bone, and heart.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974068PMC
August 2016

A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone.

J Clin Endocrinol Metab 2015 Aug 2;100(8):2841-8. Epub 2015 Jun 2.

Centre Hospitalier Régional Universitaire de Lille (S.E., J.-L.W.), Hôpital Huriez, Service d'endocrinologie et métabolisme, 59000 Lille, France; Unité Mixte de Recherche (UMR) Institut national de la santé et de la recherche médicale (Inserm) 1048 (F.S.), Institut des Maladies Métaboliques et Cardiovasculaires 31000 Toulouse, France; Equipe d'accueil 3143 (F.S.), Laboratoire de neurobiologie et transgenèse, Université d'Angers, France; Université de Lyon (F.F., R.G.), Centre National de la Recherche Scientifique (CNRS), Institut National Recherche Agronomique, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, 69008 Lyon France; Centre de recherche en Cancérologie de Lyon (V.V.-G.), UMR Inserm 1052 CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, France; Service de Biochimie Sud (V.V.-G.), Centre de Biologie Sud, Centre Hospitalier Lyon Sud, 69495 Pierre Bénite, France; Inserm (M.M., P.R.), CNRS, UMR Inserm 1083 CNRS 6214, Université d'Angers, 49100 Angers, France; Centre Hospitalier Régional Universitaire de Lille (M.H.), Centre de Biopathologie, Service de médecine nucléaire, 59000 Lille, France; UMR Inserm 1054 CNRS 5048 (W.B.), Centre de Biochimie Structurale, Universités Montpellier 1 & 2, 34000 Montpellier, France; Hôpital Necker Enfants Malades (G.P.), service d'endocrinologie pédiatrique, 75015 Paris, France; Hôpital St-Vincent de Paul (C.R.), Institut Catholique de Lille Service d'oncologie et d'hématologie, 59000 Lille, France; and Centre Hospitalier Universitaire d'Angers (P.R.), centre de référence des maladies rares de la réceptivité hormonale, 49100 Angers, France.

Context: RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio.

Objective: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated.

Design: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives.

Results: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor.

Conclusions: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.
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http://dx.doi.org/10.1210/jc.2015-1120DOI Listing
August 2015

Inadequate cortisol response to the tetracosactide (Synacthen®) test in non-classic congenital adrenal hyperplasia: an exception to the rule?

Horm Res Paediatr 2015 7;83(4):262-7. Epub 2015 Feb 7.

Service d'Endocrinologie, Gynécologie et Diabétologie Pédiatriques, Hôpital Universitaire Necker-Enfants Malades, Paris, France.

Aims: To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients.

Methods: We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl.

Results: We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone.

Conclusions: The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.
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http://dx.doi.org/10.1159/000369901DOI Listing
February 2016

Water and electrolyte disorders at long-term post-treatment follow-up in paediatric patients with suprasellar tumours include unexpected persistent cerebral salt-wasting syndrome.

Horm Res Paediatr 2014 1;82(6):364-71. Epub 2014 Nov 1.

Service d'Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.

Background: Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient.

Methods: Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery.

Results: 159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%.

Conclusions: Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care.
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http://dx.doi.org/10.1159/000368401DOI Listing
October 2015

Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort.

Horm Res Paediatr 2014 15;82(6):355-63. Epub 2014 Oct 15.

Pediatric Endocrinology, Gynecology and Diabetes, Centre des Maladies Endocriniennes Rares de la Croissance, Hôpital Universitaire Necker-Enfants Malades, Paris, France.

Background/aims: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children.

Methods: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤-2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40).

Results: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse events were reported.

Conclusions: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy.
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http://dx.doi.org/10.1159/000364807DOI Listing
October 2015

Effect of biologic treatments on growth in children with juvenile idiopathic arthritis.

J Rheumatol 2014 Jan 1;41(1):128-35. Epub 2013 Dec 1.

From the François Rabelais University, Clocheville Pediatric Hospital, Department of General Pediatrics; Pediatric Department, Centre Hospitalier Régional Universitaire (CHRU) Tours, Tours; Pediatric Immunology, Hematology and Rheumatology Unit, Pediatric Endocrinology, Biostatistics and Medical Informatics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP); Université Paris Descartes, Paris, France; University Hospital Gasthuisberg, Pediatric Rheumatology, Leuven, Belgium.

Objective: Growth retardation is a frequent complication of severe juvenile idiopathic arthritis (JIA). Biologic treatments may improve growth velocity by controlling systemic inflammation and reducing corticosteroids. Our goals were to compare growth velocity before and after the onset of biologic therapy and to determine whether the JIA subtype, the use of steroids, the requirement of one or several biologic agents, or the disease activity influenced growth velocity.

Methods: We retrospectively analyzed the growth of children with JIA who never received growth hormone treatment, who started biologic treatment before puberty, and who were followed for at least 6 months afterward.

Results: We included 100 children (33 boys). Median patient age was 7.1 years (range: 1.6-15.7) at the onset of biologic treatment and 11.0 years (range: 2.3-19.5) at the latest followup. Forty-six patients had received corticosteroid and 34 had received more than 1 biologic agent. Patient median height expressed as SD score (SDS) was 0.31 (range: -2.47 to 5.46) at disease onset, -0.24 (-3.63 to 2.90) at biologic therapy onset (p < 0.0001), and -0.15 (-4.95 to 3.52) at the latest followup (p = 0.171 compared to biologic treatment onset). Patients who required several biologics and systemic patients had a significantly lower growth velocity after the onset of biologic treatment. At the latest followup, 18% of our study group had low growth velocities and 19% were below -2SD or shorter than genetically programmed.

Conclusion: In a subset of patients, particularly systemic JIA patients and patients who required more than 1 biologic, biologic therapy may be insufficient to restore normal growth velocity.
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http://dx.doi.org/10.3899/jrheum.130311DOI Listing
January 2014

Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition.

Eur J Endocrinol 2013 Nov 1;169(5):587-96. Epub 2013 Oct 1.

AP-HP, Hôpital Pitié-Salpêtrière, Endocrinologie et Médecine de la Reproduction, 47-83, Boulevard de l'Hôpital, Paris F-75013, France.

Objectives: Our aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up.

Design And Methods: Observational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status.

Results: Most patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was <-2 SDS in 70% of treated patients at transfer and in 34% of them after 3 years of treatment. Follow-up showed improvement in lipid profile and bone mineral density in severely persistent GHD patients under GH therapy. In multivariate analysis, the associated pituitary deficits seemed stronger determinant factors of metabolic and bone status than GHD.

Conclusions: This study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.
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http://dx.doi.org/10.1530/EJE-13-0572DOI Listing
November 2013

Growth hormone therapy for children and adolescents with Prader-Willi syndrome is associated with improved body composition and metabolic status in adulthood.

J Clin Endocrinol Metab 2013 Feb 2;98(2):E328-35. Epub 2013 Jan 2.

Service de nutrition, Hôpital Pitié Salpêtrière (AP-HP), 47-83 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.

Context: Children with Prader-Willi syndrome (PWS) who receive GH treatment have improved growth and body composition; however, data are lacking for adults when treatment is discontinued after completion of growth.

Objectives: Our aim was to compare body composition and metabolic status in adults with PWS according to GH treatment in childhood and adolescence.

Design: 64 adults (mean age: 25.4 years) with a genetic diagnosis of PWS were evaluated: 20 received GH in childhood (T), which had been discontinued at the time of this study, and 44 did not receive GH (C). Mean duration of treatment in the T group was 4.4 ± 2.7 years, age at baseline was 11.8 ± 2.7 years, mean time between the end of treatment and the current evaluation was 7.0 ± 4.4 years.

Main Outcomes Measures: Dual-energy X-ray absorptiometry was used to assess body composition and fasting biological analyses evaluated metabolic status. RESULTS (MEAN ± SD): Body mass index and percentage of fat mass were significantly lower in the T group (32.4 ± 10.3 vs 41.2 ± 11.1 kg/m(2), P = 0.05 and 44.0 ± 9.6 vs 50.1 ± 7.2%, P = 0.02, respectively). Insulinemia and HOMA-IR in non-diabetic subjects were significantly lower in the T group (5.8 ± 5.9 vs 13.9 ± 11.6 μUI/ml, P = 0.03, and 1.6 ± 1.3 vs 2.7 ± 2.1, P = 0.04, respectively). Non-diabetic and diabetic subjects from the T group had a significantly lower HbA1c. Lipid profiles were similar between groups.

Conclusions: GH treatment in childhood and adolescence is associated with significantly decreased body mass index and improved body composition and metabolic status in adults with PWS at several years after discontinuing treatment.
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http://dx.doi.org/10.1210/jc.2012-2881DOI Listing
February 2013

Screening of MAMLD1 mutations in 70 children with 46,XY DSD: identification and functional analysis of two new mutations.

PLoS One 2012 30;7(3):e32505. Epub 2012 Mar 30.

Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et UM1, Montpellier, France.

More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.Seventy children with severe non-syndromic 46,XY DSD of unknown etiology were studied. One hundred and fifty healthy individuals were included as controls. Direct sequencing of the MAMLD1, AR, SRD5A2 and NR5A1 genes was performed. The transactivation function of the variant MAMLD1 proteins was quantified by the luciferase method.TWO NEW MUTATIONS WERE IDENTIFIED: p.S143X (c.428C>A) in a patient with scrotal hypospadias with microphallus and p.P384L (c.1151C>T) in a patient with penile hypospadias with microphallus. The in vitro functional study confirmed no residual transactivating function of the p.S143X mutant and a significantly reduced transactivation function of the p.P384L protein (p = 0.0032). The p.P359S, p.N662S and p.H347Q variants are also reported with particularly high frequency of the p.359T- p.662G haplotype in the DSD patients.Severe undervirilization in XY newborns can reveal mutations of MAMLD1. MAMLD1 should be routinely sequenced in these patients with otherwise normal AR, SRD5A2 and NR5A1genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032505PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316539PMC
August 2012

Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.

N Engl J Med 2011 Jun;364(23):2218-26

INSERM Unité 986, Hôpital St. Vincent de Paul, Paris, France.

The skeletal dysplasia characteristic of acrodysostosis resembles the Albright's hereditary osteodystrophy seen in patients with pseudohypoparathyroidism type 1a, but defects in the α-stimulatory subunit of the G-protein (GNAS), the cause of pseudohypoparathyroidism type 1a, are not present in patients with acrodysostosis. We report a germ-line mutation in the gene encoding PRKAR1A, the cyclic AMP (cAMP)-dependent regulatory subunit of protein kinase A, in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated subunit impairs the protein kinase A response to stimulation by cAMP; this explains our patients' hormone resistance and the similarities of their skeletal abnormalities with those observed in patients with pseudohypoparathyroidism type 1a.
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http://dx.doi.org/10.1056/NEJMoa1012717DOI Listing
June 2011

Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome.

Arthritis Rheum 2010 Jan;62(1):258-67

Assistance Publique Hôpitaux de Paris, Hôpital Necker-Enfants-Malades, INSERM U768, Université René Descartes-Paris 5, Paris, France.

Objective: Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin-1 (IL-1) processing. Anakinra, an IL-1 receptor antagonist, has been shown to be an effective treatment; however, data on long-term efficacy and safety have been sparse. This study was undertaken to assess the long-term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.

Methods: We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.

Results: There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26-42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection-site reactions.

Conclusion: The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.
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http://dx.doi.org/10.1002/art.25057DOI Listing
January 2010

Effectiveness of anastrozole and cyproterone acetate in two brothers with familial male precocious puberty.

J Pediatr Endocrinol Metab 2008 Oct;21(10):995-1002

Paediatric Endocrinology Unit, Hôpital Necker-Enfants Malades, Paris, France.

Unlabelled: Testotoxicosis is a rare form of precocious puberty caused by a constitutively activating mutation in the luteinizing hormone receptor (LHR) gene. Symptoms include rapid virilization, accelerated growth and reduced adult height. We describe a rare association of testotoxicosis with a metaphyseal chondrodysplasia called cartilage-hair hypoplasia (CHH) and report two brothers with testotoxicosis after 4 years of treatment. The brothers had a T577I mutation in the LHR gene. One brother also presented CHH. The older brother was treated with ketoconazole, then with the aromatase inhibitor anastrozole and the anti-androgen cyproterone acetate. The younger brother received this combination as first-line therapy. Clinical improvements included reductions in growth velocity and bone maturation rate, which should result in taller adult stature. Tolerance was good.

Conclusion: Combined treatment with anastrozole and cyproterone acetate is effective in improving the prognosis of adult height in testotoxicosis.
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http://dx.doi.org/10.1515/jpem.2008.21.10.995DOI Listing
October 2008

Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome.

Pediatr Res 2008 Dec;64(6):689-94

INSERM U781, Hôpital Necker-Enfants Malades, Paris, 75015, France.

Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms.
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http://dx.doi.org/10.1203/PDR.0b013e318187dd0eDOI Listing
December 2008

Scoliosis in patients with Prader-Willi Syndrome.

Pediatrics 2008 Aug 7;122(2):e499-503. Epub 2008 Jul 7.

Department of Orthopaedic Surgery, Hôpital des Enfants-Malades Assistance-Publique Hôpitaux de Paris, Faculté de Médicine Paris Descartes, Paris, France.

Objective: Our goals were to determine the prevalence and estimate the evolution of spinal deformities in patients suffering from Prader-Willi syndrome; find out which kind of spine deformity predominates regarding genotype and clinical patterns; and evaluate the affect of growth-hormone treatment on the onset and progression of spinal deformities.

Patients And Methods: This was a retrospective longitudinal, clinical, and radiologic study. One hundred forty-five children followed between 1980 and 2006 were studied in 2 referral centers for Prader-Willi syndrome. Genetic testing confirmed the diagnosis in 133 patients. Ninety-three patients (64%) received growth-hormone therapy. For statistical analysis, age-adjusted comparison between groups was performed by using multivariate logistic regression.

Results: Mean age of the patients was 10.2 +/- 6.2 years. Sixty-three (43.4%) patients were afflicted with scoliosis. Scoliosis frequency steadily rose with age, and a large majority of patients were affected at skeletal maturity (66.7%). Scoliosis prevalence was not affected by the genotype or by growth-hormone treatment. Patients with higher BMI values had an increased risk of developing a kyphotic deformity in association with scoliosis. We found a statistical association between kyphotic deformity and the need for surgical treatment.

Conclusions: Scoliosis is a major concern for patients with Prader-Willi syndrome, and a regular (annual) systematic back examination is mandated. The role of growth-hormone treatment on the natural history of scoliosis could not be determined, and careful monitoring during treatment is recommended.
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http://dx.doi.org/10.1542/peds.2007-3487DOI Listing
August 2008

Mutations in the iodotyrosine deiodinase gene and hypothyroidism.

N Engl J Med 2008 Apr;358(17):1811-8

Department of Internal Medicine, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands.

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.
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http://dx.doi.org/10.1056/NEJMoa0706819DOI Listing
April 2008
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