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Souzan Salemi, Shida Yousefi, Kurt Baltensperger, Iain C A F Robinson, Andrée Eblé, Dominique Simon, Paul Czernichow, Gerhard Binder, Emmanuel Sonnet and Primus E Mullis

Objective: Four distinct familial types of isolated GH deficiency (IGHD) are classified, of which type II, IGHD II, is the autosomal dominant inherited form. Based on clinical data, it became evident that there is a wide variability in phenotype among the various GH-1 gene alterations leading to the disorder. As subjects suffering from IGHD II caused by the specific missense mutated P89L GH (C6129T) have never been reported in detail, the aim was to analyse the impact of this mutated GH form on its clinical follow-up as well as to study its effect at the cellular level in comparison with the most common missense mutation R183H GH (G6664A).

Methods: Twelve subjects belonging to four families presenting with P89L GH were clinically compared with 17 subjects from 5 families with the R183H GH missense mutation. Further, co-localization of the wild-type (wt-type) and mutant GH forms was studied in AtT-20 cells, mouse pituitary gland, applying quantitative confocal microscopy analysis. Using immunofluorescent techniques, cells were double stained for GH and one of the following organelles: endoplasmic reticulum (anti-Grp94), Golgi (anti-βCOP) and secretory granules (anti-Rab3a). In addition, GH secretion and cell viability was analysed in detail.

Results: Importantly, as well as growth hormone deficiency, eight out of twelve subjects with the P89L mutated GH form developed other endocrine deficits and the pituitary gland became smaller over time (P < 0.05). At the cellular level, quantitative analysis of the variable mutants expressed in AtT-20 cells revealed a different extent of co-localization, different effects on GH secretion, and, therefore, a different impact on the secretory pathway which might be caused by different folding or aggregation problems necessary for sorting, packaging and/or secretion through the regulated secretory pathway.

Conclusions: Our results show that specific and detailed analyses of the different mutations identified in IGHD II may shed light on the different mechanisms of secretory pathophysiology, and may provide a better explanation of the range of clinical features associated with GH missense isoforms. Importantly, the findings in patients with P89L GH extend beyond classical IGHD and stress the need for continued clinical vigilance in IGHD II patients for the development of other hormonal deficiencies.

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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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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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Florence Roucher-Boulez, Delphine Mallet-Motak, Dinane Samara-Boustani, Houweyda Jilani, Asmahane Ladjouze, Pierre-François Souchon, Dominique Simon, Sylvie Nivot, Claudine Heinrichs, Maryline Ronze, Xavier Bertagna, Laure Groisne, Bruno Leheup, Catherine Naud-Saudreau, Gilles Blondin, Christine Lefevre, Laetitia Lemarchand and Yves Morel

Objective

Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages.

Methods

Sanger or massive parallel sequencing of NNT and patient monitoring.

Results

Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8–18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed.

Conclusions

NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.