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Elodie Fiot, Delphine Zenaty, Priscilla Boizeau, Jeremy Haigneré, Sophie Dos Santos, Juliane Léger and on behalf of The French Turner Syndrome Study Group

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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Julie Harvengt, Priscilla Boizeau, Didier Chevenne, Delphine Zenaty, Anne Paulsen, Dominique Simon, Sophie Guilmin Crepon, Corinne Alberti, Jean-Claude Carel and Juliane Léger

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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Elodie Fiot, Delphine Zenaty, Priscilla Boizeau, Jeremy Haigneré, Sophie Dos Santos, Juliane Léger and on behalf of The French Turner Syndrome Study Group

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Juliane Léger, Damir Mohamed, Sophie Dos Santos, Myriam Ben Azoun, Delphine Zénaty, Dominique Simon, Anne Paulsen, Laetitia Martinerie, Didier Chevenne, Corinne Alberti, Jean-Claude Carel and Sophie Guilmin-Crepon

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 (n = 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 (P < 0.01), etiological group (P < 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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Dominique Simon, Ibrahima Ba, Nancy Mekhail, Emmanuel Ecosse, Anne Paulsen, Delphine Zenaty, Muriel Houang, Monique Jesuran Perelroizen, Gian-Paolo de Filippo, Mariacarolina Salerno, Gilbert Simonin, Rachel Reynaud, Jean-Claude Carel, Juliane Léger and Nicolas de Roux

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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Bruno Donadille, Alexandra Rousseau, Delphine Zenaty, Sylvie Cabrol, Carine Courtillot, Dinane Samara-Boustani, Sylvie Salenave, Laurence Monnier-Cholley, Catherine Meuleman, Guillaume Jondeau, Laurence Iserin, Lise Duranteau, Laure Cabanes, Nathalie Bourcigaux, Damien Bonnet, Philippe Bouchard, Philippe Chanson, Michel Polak, Philippe Touraine, Yves Lebouc, Jean-Claude Carel, Juliane Léger and Sophie Christin-Maitre

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/m2 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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Laurence Dumeige, Livie Chatelais, Claire Bouvattier, Marc De Kerdanet, Capucine Hyon, Blandine Esteva, Dinane Samara-Boustani, Delphine Zenaty, Marc Nicolino, Sabine Baron, Chantal Metz-Blond, Catherine Naud-Saudreau, Clémentine Dupuis, Juliane Léger, Jean-Pierre Siffroi, Bruno Donadille, Sophie Christin-Maitre, Jean-Claude Carel, Regis Coutant and Laetitia Martinerie

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% (n = 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.