Publications by authors named "Delphine Zenaty"

29 Publications

  • Page 1 of 1

Screening of a large cohort of asymptomatic SDHx mutation carriers in routine practice.

J Clin Endocrinol Metab 2020 Nov 28. Epub 2020 Nov 28.

Sorbonne university, department of nuclear medicine, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers who would benefit from screening protocols.

Objective: To define tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least one imaging work-up were enrolled.

Results: Initial work-up including anatomical (98% of subjects [97-100 % according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from one to nine subsequent follow-up assessments (mean: 1.9/patient) with a median follow-up time of 5 [1-13] years. Anatomical (86% [49-100 %]) and/or functional imaging ((36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 PGL, including 45 head and neck PGL, 2 PCC, 1 GIST), were detected in 50 patients (22 (13%) SDHB, 1 (3.2%) SDHC and 27 (57%) SDHD) with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutations carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
November 2020

Factors Affecting Loss to Follow-Up in Children and Adolescents with Chronic Endocrine Conditions.

Horm Res Paediatr 2019 5;92(4):254-261. Epub 2020 Feb 5.

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Department of Pediatric Endocrinology and Diabetology, Reference Center for Growth and Development Endocrine Diseases, Paris, France.

Objective: Most children with endocrine diseases require long-term continuity of care. We investigated the prevalence of loss to follow-up (LTFU) in pediatric patients with chronic endocrine diseases and the risk factors associated with LTFU.

Methods: This observational cohort study included all children with chronic endocrine diseases included in the database of a single academic pediatric care center over a period of 8 years. LTFU was defined as a lack of attendance at clinical visits for over 2 years, for unknown reasons.

Results: LTFU was recorded for 154 of the 1,067 patients included (14%). Median age at diagnosis was 5.8 (0.3-11.8) vs. 1.2 (0.0-6.9) years, and age at last visit was 14.1 (9.7-16.1) vs. 11.7 (6.1-15.8) years, for the LTFU and no-LTFU groups, respectively. In multivariate analysis, the risk of LTFU increased with age at diagnosis (OR 1.18; 95% CI 1.12-1.24) and was higher for patients diagnosed before 2006 (vs. after 2006; OR 4.80; 95% CI 3.00-7.66), with fewer visits in the last 3 years (OR 0.72; 95% CI 0.65-0.80; p < 0.0001) and a lower health insurance classification (OR 1.79; 95% CI 1.10-2.89; p = 0.02). The risk of LTFU was higher for patients with isolated growth hormone deficiency than for those with other endocrine conditions, such as multiple pituitary deficiencies, hypogonadotropic hypogonadism, Turner syndrome, or thyroid, adrenal, or gonadal disorders (OR 5.24; 95% CI 1.13-24.37; p = 0.03).

Conclusion: This study provides the first epidemiological data for LTFU in children and adolescents with chronic endocrine diseases. It should facilitate the targeting of interventions to improve adherence to medical care and healthcare organization during the pediatric period.
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http://dx.doi.org/10.1159/000505517DOI Listing
May 2020

X chromosome gene dosage as a determinant of congenital malformations and of age-related comorbidity risk in patients with Turner syndrome, from childhood to early adulthood.

Eur J Endocrinol 2019 06;180(6):397-406

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Pediatric Endocrinology Diabetology Department, Reference Centre for Endocrine Growth and Development Diseases, Paris, France.

Objective Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup. Design and methods This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87). Results Median age was 9.4 (3.7-13.7) years at first evaluation and 16.8 (11.2-21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders. Conclusion These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.
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http://dx.doi.org/10.1530/EJE-18-0878DOI Listing
June 2019

Positive Impact of Genetic Test on the Management and Outcome of Patients With Paraganglioma and/or Pheochromocytoma.

J Clin Endocrinol Metab 2019 04;104(4):1109-1118

Équipe Labellisée par la Ligue Contre le Cancer, INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France.

Context: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL.

Objective: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL.

Design: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis.

Results: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases as well as lower metastatic spread were observed in genetic patients. Of note, these differences were reversed in the historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival rate than historic patients (P = 0.0127).

Conclusion: Altogether, our data suggest that early knowledge of genetic status had a positive impact on the management and clinical outcome of patients with a germline SDHx or VHL mutation.
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http://dx.doi.org/10.1210/jc.2018-02411DOI Listing
April 2019

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty.

Eur J Endocrinol 2018 Dec;179(6):373-380

Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Endocrinology-Diabetology Department, Reference Center for Endocrine Growth and Developmental Diseases, Paris, France.

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.
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http://dx.doi.org/10.1530/EJE-18-0613DOI Listing
December 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

Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study.

Thyroid 2018 08 30;28(8):959-967. Epub 2018 Jul 30.

1 Department of Pediatric Endocrinology Diabetology, Reference Centre for Endocrine Growth and Development Diseases, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital , Paris, France .

Background: An increase in the incidence of congenital hypothyroidism (CH) with a normally located gland has been reported worldwide. Affected individuals display transient or permanent CH during follow-up in childhood. This study aimed to determine the prevalence of transient CH and to investigate the possibility of distinguishing between transient and permanent CH in early infancy.

Methods: This observational cohort study included all patients identified by systematic neonatal screening for CH in the northern Parisian region between 2002 and 2012 and treated for CH with a normally sited gland. A standardized data collection form was completed prospectively at diagnosis. Patients were classified during follow-up as having transient or permanent CH.

Results: Of the 92 patients initially treated for CH with a normally located gland during the neonatal period, 49 (54%) had a transient form of CH after the cessation of levothyroxine (LT4) treatment at 1.5 (0.6-3.2) years of age. Multivariate analysis revealed that transient CH was associated with a lower likelihood of having a first-degree family history of CH (p = 0.03) and a lower LT4 dose at six months of age (p = 0.03) than permanent CH. Sex, ethnicity, neonatal problems (e.g., prematurity, being small for gestational age, and/or neonatal distress), iodine status, coexisting malformations, initial CH severity, and thyroid morphology at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 3.2 μg/kg/day for LT4 dose requirement at six months of age had a sensitivity of 71% and a specificity of 79% for predicting transient CH, with values below this threshold considered predictive of transient CH.

Conclusion: In patients with CH and a normally located gland, these findings highlight the need to evaluate LT4 dose requirements early, at six months of age, particularly in patients with no family history of CH, for early identification of the approximately 50% of patients for whom treatment should be stopped.
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http://dx.doi.org/10.1089/thy.2018.0154DOI Listing
August 2018

SFE/SFEDP adrenal insufficiency French consensus: Introduction and handbook.

Ann Endocrinol (Paris) 2018 Feb 12;79(1):1-22. Epub 2018 Jan 12.

Service d'endocrinologie diabétologie pédiatrique, hôpital Robert-Debré, centre de référence des maladies endocriniennes rares de la croissance et du développement, université Paris Diderot, Assistance publique-Hôpitaux de Paris, 48, boulevard Sérurier, 75019 Paris, France.

The French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under- and over-dosage and on the diagnosis of associated auto-immune disorders.
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http://dx.doi.org/10.1016/j.ando.2017.12.001DOI Listing
February 2018

Group 6. Modalities and frequency of monitoring of patients with adrenal insufficiency. Patient education.

Ann Endocrinol (Paris) 2017 Dec 1;78(6):544-558. Epub 2017 Dec 1.

Service d'endocrinologie diabétologie pédiatrique, hôpital Robert-Debré, université Paris-Diderot, centre de référence des maladies endocriniennes rares de la croissance et du développement, Assistance publique-hôpitaux de Paris, 48, boulevard Sérurier, 75019 Paris, France.

Patients with adrenal insufficiency require regular, specialised monitoring in order to optimise their replacement therapy, to detect signs of under- and over-dosage, and to examine for possible associated disorders (auto-immune disorders in the case of auto-immune primary adrenal insufficiency either isolated or as part of auto-immune polyendocrinopathy syndrome type 1; illnesses with underlying monogenic causes). The transition period between adolescence and adulthood represents an added risk of a breakdown in monitoring which requires particular attention from medical teams and coordination between adult and pediatric medical teams. It is essential to encourage patient autonomy in the management of their illness, notably their participation in treatment education programs, in particular programs that target avoidance of, or early treatment of acute adrenal insufficiency. The principal educational objectives for patients in such programs are: to be in possession of, and carry the necessary tools for their treatment in an emergency; to be able to identify situations of increased risk and the early signs of adrenal crisis; to know how to adjust their oral glucocorticoid treatment; to be capable of administering hydrocortisone by subcutaneous injection; to be able to predict and therefore adjust treatment to different situations (heat, physical exercise, travel) and to be able to correctly use the appropriate resources of the healthcare services. Other programs could also be developed to respond to needs and expectations of patients, notably concerning the adjustment of hydrocortisone dosage to avoid overdose in the context of chronic fatigue syndrome.
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http://dx.doi.org/10.1016/j.ando.2017.10.009DOI Listing
December 2017

Group 1. Epidemiology of primary and secondary adrenal insufficiency: Prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality.

Ann Endocrinol (Paris) 2017 Dec 27;78(6):490-494. Epub 2017 Nov 27.

Service des maladies endocriniennes et métaboliques, hôpital Cochin, CHU Paris Centre, 75014 Paris, France.

The prevalence of primary adrenal insufficiency is estimated at between 82-144/million, with auto-immunity being the most common cause in adults and genetic causes, especially enzyme defects, being the most common cause in children. The prevalence of secondary adrenal deficiency is estimated to be between 150-280/million. The most frequent occurrence is believed to be corticosteroid-induced insufficiency, despite the incidence of clinically relevant deficiency after cessation of glucocorticoid treatment being widely debated. Data on mortality in adrenal insufficiency are contradictory, with studies from Sweden suggesting a two-fold increase in comparison to the general population, but this is not consistently reported in all studies. However, increased mortality has been consistently reported in young patients, associated with infection and/or acute adrenal insufficiency. Acute adrenal deficiency (adrenal crisis) occurs in primary as well as secondary adrenal insufficiency. Its incidence, mostly determined in retrospective studies, is estimated in Europe at 6-8/100 patients/year. A prospective study reported 0.5 deaths/100 patient-years from adrenal crisis. Long-term morbidity of adrenal insufficiency is not well-established, the increased cardiovascular risk or bone demineralization which are not consistently reported may also be due to a supraphysiological glucocorticoid replacement therapy. However, alteration in quality of life, both in physical and mental health components, has been demonstrated by several studies in both primary and secondary adrenal insufficiency.
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http://dx.doi.org/10.1016/j.ando.2017.10.010DOI Listing
December 2017

Group 5: Acute adrenal insufficiency in adults and pediatric patients.

Ann Endocrinol (Paris) 2017 Dec 23;78(6):535-543. Epub 2017 Nov 23.

Service d'endocrinologie et des maladies de la reproduction, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, AP-HP, 94275 Le Kremlin-Bicêtre, France; Inserm 1185, faculté médecine Paris-Sud, université Paris-Sud, université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1016/j.ando.2017.10.008DOI Listing
December 2017

Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children.

Eur J Endocrinol 2017 Sep;177(3):267-276

Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du développement, Paris, France.

Context: Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety.

Objective: To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels.

Design, Patients And Methods: This observational cohort study included all patients ( = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data.

Results: Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose ( < 0.01), etiological group ( < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect.

Conclusions: These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.
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http://dx.doi.org/10.1530/EJE-17-0215DOI Listing
September 2017

Mutations in BOREALIN cause thyroid dysgenesis.

Hum Mol Genet 2017 02;26(3):599-610

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

Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.
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http://dx.doi.org/10.1093/hmg/ddw419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311960PMC
February 2017

A 6-Month Trial of the Efficacy and Safety of Triptorelin Pamoate (11.25 mg) Every 3 Months in Children with Precocious Puberty: A Retrospective Comparison with Triptorelin Acetate.

Horm Res Paediatr 2016 7;86(3):188-195. Epub 2016 Sep 7.

Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Background/aims: To evaluate the efficacy and safety of a triptorelin pamoate (11.25 mg) 3-month formulation in the management of central precocious puberty (CPP) (TP Study) and to retrospectively compare it with a triptorelin acetate (11.25 mg) 3-month formulation (TA Study).

Methods: We conducted two phase III, multicentre, single-stage, non-comparative, open-label studies. In the TP Study, patients with CPP received an intramuscular injection of triptorelin pamoate 11.25 mg at baseline and 3 months after baseline. Hormonal changes as well as safety and efficacy endpoints were measured at baseline, 3 months, and 6 months.

Results: The baseline characteristics of the 37 patients in the TP Study were similar to those of the TA Study population. A suppressed luteinising hormone (LH) response (LH peak ≤3 IU/l) to the gonadotrophin-releasing hormone test at 3 months (primary endpoint) occurred in 83.8 and 82.8% of the cases in the TP and the TA Study, respectively. At 6 months, a suppressed LH response occurred in 86.5 and 96.8% of the cases in the TP and the TA Study, respectively. Pubertal development was slowed in both studies. Adverse events were mild to moderate and resolved without sequelae in the TP Study.

Conclusion: Triptorelin pamoate 11.25 mg administered at 3-month intervals is an effective and well-tolerated treatment in patients with CPP. The efficacy and safety profiles appear similar to those reported in the literature for triptorelin acetate 11.25 mg. © 2016 S. Karger AG, Basel.
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http://dx.doi.org/10.1159/000448840DOI Listing
April 2017

X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome.

Eur J Endocrinol 2016 Sep;175(3):X1

Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019, Paris, France Université Paris DiderotSorbonne Paris Cité, F-75019 Paris, France Institut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, France.

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http://dx.doi.org/10.1530/EJE-15-1000eDOI Listing
September 2016

Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome.

Hum Reprod 2016 Apr 13;31(4):782-8. Epub 2016 Feb 13.

Université Pierre et Marie Curie, F-75012 Paris, France Service d'Endocrinologie et Maladies de la Reproduction, Centre de référence des Maladies Endocriniennes Rares de la Croissance (CRMERC), Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France

Study Question: What are the prevalence and the outcomes of spontaneous pregnancies (SP) in a large cohort of French women with Turner syndrome (TS)?

Summary Answer: Amongst 480 women with TS, 27 women (5.6%) had a total of 52 SP, with 30 full-term deliveries for 18 women.

What Is Known Already: Primary ovarian insufficiency is a classic feature of TS. So far, few studies have evaluated the rate of SP in these patients.

Study Design, Size, Duration: The French Ministry of Health set up a National Reference Centre for Rare Growth Disorders (CRMERC), including TS. We studied a cohort of adult TS patients from seven endocrine units (Saint-Antoine, Pitié-Salpêtrière, Bicêtre, Lyon, Marseille, Brest, Reims Hospitals) belonging to this centre, between January 1999 and January 2014.

Participants/materials, Setting, Methods: A total of 480 adult patients with TS were included. The patients' clinical characteristics, karyotypes and reproductive histories had been collected, after informed consent, in a web database called CEMARA. Our reference population was issued from a database belonging to the French Health Ministry, collecting pregnancy outcomes in the French general population. In order to find predictive characteristics of SP, TS with spontaneous pregnancies were compared with non-pregnant TS patients from our cohort.

Main Results And The Role Of Chance: There were 27 patients (5.6%) who had a total of 52 SP. The two predictive factors which correlated with occurrence of a SP were spontaneous menarche and mosaic karyotype. The median delay to conception was 6 months (range 0-84). Miscarriage occurred in 16 pregnancies, 30.8% versus 15% in the general French population (P < 0.01). The remaining pregnancy outcomes were legal abortion (n = 2), medical interruption (n = 3), intrauterine fetal death (n = 1) and delivery at term (n = 30). Caesarean section rates were higher than in the general population, respectively 46.7% versus 21% (P < 0.001). Pregnancy-induced hypertensive disorders (PHDs) occurred in four cases (13.3%), including two cases of mild pre-eclampsia (6.7%). Neither aortic root dilatation nor aortic dissection were observed. The median birthweight was 3030 g (range 2020-3460). Two cases of TS were identified in the 17 daughters issued from this cohort.

Limitations, Reasons For Caution: It would have been interesting to evaluate AMH levels and SP occurrence, as a predictive factor. Unfortunately, hormonal measurements were missing for some patients. Prospective studies are necessary to display prognostic values of AMH for SP and thus better target fertility preservation programmes in TS patients.

Wider Implications Of The Findings: This study suggests that pregnancy outcomes in SPs are more favourable than those after oocyte donation in TS patients. However, the risk of fetal chromosomal abnormalities remains high. Our study will be useful in order to give patients with TS, their families, paediatricians and physicians involved in reproduction, better counselling concerning their fertility.

Study Funding/competing Interests: Funding was provided by the Association pour la recherche Claude Bernard, Paris France All authors claim no competing interests.

Trial Registration Number: NA.
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http://dx.doi.org/10.1093/humrep/dew012DOI Listing
April 2016

X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome.

Eur J Endocrinol 2016 Mar 14;174(3):281-8. Epub 2015 Dec 14.

Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, FranceAP-HPHôpital Robert Debré, Unit of Clinical Epidemiology, F-75019, Paris, FranceInsermCIC-EC 1426, F-75019 Paris, France Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, FranceAP-HPHôpital Robert Debré, Unit of Clinical Epidemiology, F-75019, Paris, FranceInsermCIC-EC 1426, F-75019 Paris, France Assistance Publique-Hôpitaux de ParisHôpital Robert Debré, Service d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, INSERM U 1141, 48 Bd Sérurier, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (Inserm)Unité 1141, DHU Protect, F-75019 Paris, FranceAP-HPHôpital Robert Debré, Unit of Clinical Epidemiology, F-75019, Paris, FranceInsermCIC-EC 1426, F-75019 Paris, France

Objective: Short stature is a key aspect of the phenotype of patients with Turner syndrome (TS). SHOX haploinsufficiency is responsible for about two-thirds of the height deficit. The aim was to investigate the effect of X-chromosome gene dosage on anthropometric parameters at birth, spontaneous height, and adult height (AH) after growth hormone (GH) treatment.

Design: We conducted a national observational multicenter study.

Methods: Birth parameter SDS for gestational age, height, and AH before and after GH treatment respectively, and height deficit with respect to target height (SDS) were classified by karyotype subgroup in a cohort of 1501 patients with TS: 45,X (36%), isoXq (19%), 45,X/46,XX (15%), XrX (7%), presence of Y (6%), or other karyotypes (17%).

Results: Birth weight, length (P<0.0001), and head circumference (P<0.001), height and height deficit with respect to target height (SDS) before GH treatment, at a median age of 8.8 (5.3-11.8) years and after adjustment for age and correction for multiple testing (P<0.0001), and AH deficit with respect to target height at a median age of 19.3 (18.0-21.8) years and with additional adjustment for dose and duration of GH treatment (P=0.006), were significantly associated with karyotype subgroup. Growth retardation tended to be more severe in patients with XrX, isoXq, and, to a lesser extent, 45,X karyotypes than in patients with 45,X/46,XX karyotypes or a Y chromosome.

Conclusion: These data suggest that haploinsufficiency for an unknown Xp gene increases the risk of fetal and postnatal growth deficit and short AH with respect to target height after GH therapy.
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http://dx.doi.org/10.1530/EJE-15-1000DOI Listing
March 2016

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.

Eur J Endocrinol 2016 Jan 1;174(1):1-8. Epub 2015 Oct 1.

AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la Timone, Aix-Marseille Université, Marseille F-13385, France AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la T

Context And Objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.

Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.

Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01).

Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.
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http://dx.doi.org/10.1530/EJE-15-0488DOI Listing
January 2016

Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.

J Bone Miner Res 2016 Mar 20;31(3):498-513. Epub 2015 Oct 20.

EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, Dental School Paris Descartes University, Sorbonne Paris Cité, France.

Claudin-16 protein (CLDN16) is a component of tight junctions (TJ) with a restrictive distribution so far demonstrated mainly in the kidney. Here, we demonstrate the expression of CLDN16 also in the tooth germ and show that claudin-16 gene (CLDN16) mutations result in amelogenesis imperfecta (AI) in the 5 studied patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). To investigate the role of CLDN16 in tooth formation, we studied a murine model of FHHNC and showed that CLDN16 deficiency led to altered secretory ameloblast TJ structure, lowering of extracellular pH in the forming enamel matrix, and abnormal enamel matrix protein processing, resulting in an enamel phenotype closely resembling human AI. This study unravels an association of FHHNC owing to CLDN16 mutations with AI, which is directly related to the loss of function of CLDN16 during amelogenesis. Overall, this study indicates for the first time the importance of a TJ protein in tooth formation and underlines the need to establish a specific dental follow-up for these patients.
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http://dx.doi.org/10.1002/jbmr.2726DOI Listing
March 2016

Triiodothyronine-predominant Graves' disease in childhood: detection and therapeutic implications.

Eur J Endocrinol 2015 Jun 12;172(6):715-23. Epub 2015 Mar 12.

Assistance Publique-Hôpitaux de ParisService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, F-75019 Paris, FranceINSERMCIC 1426, UMR 1123, Paris, FranceAssistance Publique-Hôpitaux de ParisService de Biochimie-HormonologieAssistance Publique-Hôpitaux de ParisUnité d'Épidémiologie Clinique, Hôpital Robert Debré, Paris, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, F-75019 Paris, FranceINSERMCIC 1426, UMR 1123, Paris, FranceAssistance Publique-Hôpitaux de ParisService de Biochimie-HormonologieAssistance Publique-Hôpitaux de ParisUnité d'Épidémiologie Clinique, Hôpital Robert Debré, Paris, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, F-75019 Paris, FranceUniversité Paris DiderotSorbonne Paris Cité, F-75019 Paris, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, F-75019 Paris, FranceINSERMCIC 1426, UMR 1123, Paris, FranceAssistance Publique-Hôpitaux de ParisService de Biochimie-HormonologieAssistance Publique-Hôpitaux de ParisUnité d'Épidémiologie Clinique, Hôpital Robert Debré, Paris, France.

Objective: To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children.

Design: We conducted a university hospital-based observational study.

Methods: All patients with GD followed for more than 1 year between 2003 and 2013 (n=60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD.

Results: Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II.

Conclusion: Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up.
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http://dx.doi.org/10.1530/EJE-14-0959DOI Listing
June 2015

Cardiovascular findings and management in Turner syndrome: insights from a French cohort.

Eur J Endocrinol 2012 Oct 16;167(4):517-22. Epub 2012 Jul 16.

Department of Endocrinology, Centre de référence des Maladies Endocriniennes Rares de la Croissance (CMERC), Assistance Publique - Hôpitaux de Paris, Saint Antoine Hospital, 184 Rue du Faubourg Saint-Antoine, 75011 Paris, France.

Objective: Congenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults.

Design/methods: We recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300).

Results: Informative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0-60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th-75th percentiles: 15-30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7-30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m(2) in 39% of the cohort.

Conclusion: Our study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.
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http://dx.doi.org/10.1530/EJE-12-0434DOI Listing
October 2012

Turner syndrome and pregnancy: clinical practice. Recommendations for the management of patients with Turner syndrome before and during pregnancy.

Eur J Obstet Gynecol Reprod Biol 2010 Sep 1;152(1):18-24. Epub 2010 Jul 1.

University Hospital Cochin - Saint-Vincent de Paul, Assistance Publique-Hopitaux de Paris, Université René Descartes, Boulevard de Port Royal, 75005 Paris, France.

Following the death in France by acute aortic dissection of two women with Turner syndrome who were pregnant following oocyte donation, the Director of the French Biomedicine Agency (Agence de la biomédecine) sent a letter to the President of the French College of Obstetricians and Gynaecologists (FCOG). He requested the College's expertise in reviewing point-by-point the cases and risk factors and in determining whether there are grounds to propose additional measures complementary to the recommendations made by the Haute autorité de santé or French National Authority for Health (HAS) in 2008 in terms of indication and monitoring of patients. A joint practice committee of the FCOG, the French Cardiologic Society, the French Chest and Cardiovascular Surgery Society, the French Society of Anaesthesia and Intensive Care, the French Endocrine Society, the French study group for oocyte donation, and the Biomedicine Agency defined the exact questions to be put to the experts, chose these experts, followed them up and drafted the synthesis of recommendations resulting from their work. The questions concerned the check-up before pregnancy of Turner patients, contraindication and acceptance of pregnancy, information for the patients, and recommendations for antenatal care, delivery and postnatal follow-up.
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http://dx.doi.org/10.1016/j.ejogrb.2010.05.019DOI Listing
September 2010

Dental agenesis in Kallmann syndrome individuals with FGFR1 mutations.

Int J Paediatr Dent 2010 Jul;20(4):305-12

Paediatric Dentistry, Garancière Hotel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris Diderot University, France.

Background: Kallmann syndrome (KS) is a rare genetic disorder characterised by central hypogonadism with a lack of sense of smell and in some cases renal aplasia, deafness, syndactyly, cleft lip/palate, and dental agenesis. To date, five genes for KS have been identified: KAL1, located on the X chromosome, and FGFR1, PROKR2, PROK2 and FGF8, which are involved in autosomally transmitted forms of KS.

Aim: The study characterised the dental ageneses of individuals with KS associated with mutations in the FGFR1 gene.

Design: Six individuals displaying dental agenesis were included. Clinical and radiological dental evaluations as well as medical anamneses were carried out.

Results: Microdontia, screwdriver-shaped mandibular incisors, thin molar roots, and patterns of dental agenesis in both dentitions were observed. One to nine teeth were missing, most frequently, in descending order, lateral mandibular incisors, second premolars of upper and lower jaws, and lateral maxillary incisors. The pattern of dental agenesis is associated with four new mutations in the FGFR1 gene.

Conclusion: Dental agenesis may be a clinical feature of Kallmann syndrome caused by a mutation in the FGFR1 gene. These findings highlight the role that odontologists can play in the early diagnosis and treatment of gonadotropic deficiency.
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http://dx.doi.org/10.1111/j.1365-263X.2010.01056.xDOI Listing
July 2010

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration.

Reprod Biol Endocrinol 2010 Mar 19;8:28. Epub 2010 Mar 19.

Service d'Hormonologie, Hôpital Lapeyronie, CHU Montpellier, and Université Montpellier 1, France.

Background: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.

Methods: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations.

Results: Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration.

Conclusions: The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.
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http://dx.doi.org/10.1186/1477-7827-8-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848664PMC
March 2010

[Precocious pubertal].

Rev Prat 2008 Jun;58(12):1317-23

Service d'endocrinologie-diabétologie pédiatrique, centre de référence des maladies endocriniennes rares de la croissance, hôpital Robert-Debré, Université Paris-Diderot Paris-7, 75935 Paris Cedex 19, France.

Precocious pubertal is frequent and should lead to a rigorous evaluation. It is important to precisely evaluate the timing of pubertal development, and to search for an hypothalamic lesion in cases of central precocious puberty. It is also important to recognize that many cases of precocious puberty will not progress and therefore do not need treatment. When central precocious puberty has been confirmed, GnRH agonists should be considered. Management issues, as well as long term results of these treatments are presented.
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June 2008

Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study.

Hum Reprod 2007 Dec 16;22(12):3255-61. Epub 2007 Oct 16.

Service d'Hormonologie, Hôpital Lapeyronie, CHU Montpellier, 34295 Montpellier cedex 5, France.

BACKGROUND Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis and reproduction. Recently, haploinsufficiency of SF1 has been described in several 46,XY individuals with mild gonadal dysgenesis and impaired androgenization, but normal adrenal function, suggesting that dosage-sensitive or domain-specific effects of SF1 action are important in human testicular development and function. Our objective was to investigate whether partial defects in SF1 function might be associated with milder male reproductive phenotypes, such as bilateral anorchia ('vanishing testis syndrome') and micropenis. METHODS This study involved mutational analysis of NR5A1 in 24 individuals with bilateral anorchia and micropenis from the French Collaborative Anorchia study, as well as in vitro functional studies of SF1-dependent transcriptional activation and computer modeling. RESULTS A novel heterozygous missense mutation (V355M) in SF1 was found in one boy with a micropenis and testicular regression syndrome. This non-synonymous change was found to affect a highly conserved amino acid within helix 7 of the ligand-binding domain of SF1. This V355M mutation did not affect stability or nuclear localization, but did result in an approximately 50% reduction in SF1 activity in several different assay systems. CONCLUSIONS In conclusion, heterozygous partial loss of function mutations in SF1 may be associated with bilateral anorchia ('vanishing testis syndrome') and micropenis in humans.
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http://dx.doi.org/10.1093/humrep/dem278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990861PMC
December 2007

Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1).

Mol Cell Endocrinol 2006 Jul 6;254-255:78-83. Epub 2006 Jun 6.

Assistance Publique Hôpitaux de Paris, Robert Debre Hospital Paediatric Endocrinology unit, Robert Debré Hospital, Paris, France.

Kallmann syndrome characterised by hypogonadotropic hypogonadism (HH) and anosmia is genetically heterogeneous with X-linked, autosomal dominant and autosomal recessive forms. The autosomal dominant form due to loss of function mutation in the fibroblast growth factor receptor 1 (FGFR1) accounts for about 10% of cases. We report here three paediatric cases of Kallmann syndrome with unusual phenotype in two unrelated patients with severe ear anomalies (hypoplasia or agenesis of external ear) associated with classical features, such as cleft palate, dental agenesis, syndactylia, micropenis and cryptorchidism. We found de novo mutation in these two patients (Cys178Ser and Arg622Gly, respectively), and one inherited Arg622Gln mutation with intrafamilial variable phenotype. These genotype-phenotype correlations indicate that paediatric phenotypic expression of FGFR1 loss of function mutations is highly variable, the severity of the oro-facial malformations at birth does not predict gonadotropic function at the puberty and that de novo mutations of FGFR1 are relatively frequent.
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http://dx.doi.org/10.1016/j.mce.2006.04.006DOI Listing
July 2006

Presence of magnetic resonance imaging abnormalities of the hypothalamic-pituitary axis is a significant determinant of the first 3 years growth response to human growth hormone treatment in prepubertal children with nonacquired growth hormone deficiency.

Clin Endocrinol (Oxf) 2003 May;58(5):647-52

Paediatric Endocrinology Unit, Radiology Department, Paris, France.

Objective: The factors influencing the highly variable growth response to GH treatment in GH-deficient children are not fully understood. Despite a real benefit with GH treatment in term of growth response, most of these patients attain a mean adult height below their target height and the strategy to optimise final height has to be improved. The aim of this study was to investigate whether the presence of congenital abnormalities of the hypothalamic-pituitary axis on magnetic resonance imaging (MRI) could be a determinant of the growth response in nonacquired prepubertal GH-deficient children, and to identify which pretreatment variables most significantly affect the first 3 years growth response to human GH (hGH) therapy.

Patients And Methods: The growth response to hGH treatment (0.55 +/- 0.1 IU/kg/week) was evaluated in 69 prepubertal children with nonacquired GH deficiency, according to the absence (group A: chronological age = 4.8 +/- 2.4 years, n= 37) or the presence (group B: chronological age = 3.4 +/- 2.7 years, n= 32) of developmental abnormalities on cerebral magnetic imaging and, after controlling for GH dose, age, height, height velocity (SDS) and body mass index at start of treatment, maximum stimulated GH peak concentration, GH deficiency type (isolated vs. multiple deficiency), parental height, size at birth and sex.

Results: After 3 years of treatment, the mean height gain was significantly higher in patients of group B vs. group A (2.2 +/- 1.3 vs. 1.6 +/- 1 SDS; P < 0.05). In a multiple regression analysis, age (r2 = 0.19, negatively correlated), pretreatment height velocity (r2 = 0.11, negatively correlated), GH dose (r2 = 0.05, positively correlated) and presence of magnetic resonance imaging developmental abnormalities (r2 = 0.05, positively correlated) were found to significantly explain 40% of the variability in growth response.

Conclusions: The detection of congenital abnormalities in the hypothalamic-pituitary area on MRI is more important than the level of maximum stimulated GH to predict the growth response to hGH treatment in prepubertal nonacquired GH-deficient children. Although the persistence of GH deficiency remains to be confirmed during follow-up by reassessment of GH secretion in isolated GH-deficient patients with normal MRI findings, further studies are needed to evaluate whether an increased hGH dose in these patients could improve long-term growth response.
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May 2003