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

Cessans, Catie; Ehlinger, Virginie; Arnaud, Catherine; Yart, Armelle; Capri, Yline; Barat, P.; Cammas, B.; Lacombe, Didier; Coutant, Régis; David, Albert; S, Baron; Weill, Jacques; Leheup, Bruno; Nicolino, Marc; Salles, Jean‐Pierre; Verloès, Alain; Tauber, Maïthé; Cavé, Hélène; Edouard, Thomas

doi:10.1530/eje-15-0922

Cited by 47 publications

(58 citation statements)

References 36 publications

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“…It has been suggested that the association between body fat and age of pubertal onset in boys may be nonlinear with delayed puberty seen in very lean as well as in very obese boys (25). As previously reported in NS (19,29,30), our patients displayed a lean phenotype with a BMI in the lower normal range which may influence the timing of puberty. The relationship between fat mass and puberty may be mediated by several factors, including leptin, the levels of which are very low in our patients.…”

Section: Discussionsupporting

confidence: 74%

“…Interestingly, Sertoli cell markers levels significantly varied according to the genotype with lower levels in NS-PTPN11 and RAF1 patients than in SOS1 patients. Of note, the same impact of genes was found for growth impairment, infants with SOS1 mutations being less short than those with NS-PTPN11 or RAF1 mutations (19). These differences between genotypes may be explained by variations in the degree of activation of the RAS/ERK signalling pathway or by differential, genotype-dependent, tissue specificity.…”

Section: Discussionmentioning

confidence: 70%

“…To our knowledge, only one study has investigated markers of testicular function, such as anti-Müllerian hormone (AMH) and inhibin B, in NS prepubertal boys (12). Moreover, the better knowledge of the genetic bases of NS made possible to look for genotypephenotype correlations, notably with cardiac, growth and haematological defects (1,19), but these correlations have not been investigated for gonadal function. In the present study, we aimed to describe the gonadal function of boys with NS and NSML according to their phenotype, notably the presence or not of cryptorchidism and evaluate whether mutations in the different genes involved in NS and NSML may have differential impact.…”

Section: Introductionmentioning

confidence: 99%

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Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Moniez

Pienkowski

Lepage

et al. 2018

European Journal of Endocrinology

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Context: Abnormalities in the hypothalamo-pituitary-gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children.Objective: The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design: It is a retrospective chart review. Patients and methods: A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results: Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4-15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = −0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: −0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: −1.1 ± 1.2; P < 0.001) compared with the general population, suggesting a Sertoli cell dysfunction. Lower AMH and inhibin B levels were found in NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions: NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Moniez

Pienkowski

Lepage

et al. 2018

European Journal of Endocrinology

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“…gressive growth failure in infancy, sustained growth in childhood (below -2 standard deviation scores [SDS] of the growth curve of normal children), delayed growth spurt in puberty, and short stature in adulthood (just below -2 SDS) [1,[6][7][8][9].…”

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confidence: 99%

Efficacy and safety of two doses of Norditropin<sup>®</sup> (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients

et al. 2018

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Abstract. This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin ® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3-<11 years (boys) or 3-<10 years (girls) with Noonan syndrome were randomized to receive GH 0.033 mg/kg/day (n = 25, mean age 6.57 years, 11 females) or 0.066 mg/kg/day (n = 26, mean age 6.06 years, eight females) for 104 weeks. Change in height standard deviation score (HSDS) from baseline was analyzed based on an ANCOVA model. Baseline HSDS was -3.24. Estimated change in HSDS [95% CI] after 104 weeks' treatment was 0.84 [0.66, 1.02] and 1.47 [1.29, 1.64] for the lower and higher doses, respectively; estimated mean difference 0.63 [0.38, 0.88], p < 0.0001. Rates and patterns of adverse events (AEs) were similar between groups. Most were mild and reported as unlikely to be related to Norditropin ® . There were no withdrawals due to AEs. Insulin-like growth factor-I SDS increased from -1.71 to -0.64 (0.033 mg/kg/day) and to 0.63 (0.066 mg/kg/day). HbA 1c increased slightly (0.033 mg/kg/day: +0.14%; 0.066 mg/kg/day: +0.13%); glucose profiles were almost unchanged; insulin profiles increased in both groups in the oral glucose tolerance test. There were no clinically significant abnormal electrocardiogram or echocardiography findings. We conclude that Norditropin ® at doses of 0.033 mg/kg/day or 0.066 mg/kg/day for 104 weeks increases height in Japanese children with short stature due to Noonan syndrome, with a favorable safety profile. The effect was greater with 0.066 mg/kg/day compared with 0.033 mg/kg/day.

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“…Currently, most phenotypic analyses in RASopathies are based on comparison at the gene level (23)(24)(25)(26), but there is high phenotypic heterogeneity within patients having mutations in the same gene (12). Independent of genetic background, it is important to know whether some mutations can cause more severe phenotypes than others.…”

mentioning

confidence: 99%

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Jindal

Goyal

Yamaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.T he Ras/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway is involved in essentially all aspects of organismal development, from the first cell divisions in the early embryo to postnatal development and growth (1-3). Given its critical function, it is not surprising that deregulated Ras/ MAPK signaling, resulting from either genetic or environmental perturbations, can lead to developmental abnormalities. A large class of such abnormalities, known as RASopathies, is associated with activating germ-line mutations in many components of the Ras pathway (4). Estimated to affect 1/1,000 human births, these abnormalities are characterized by a broad spectrum of phenotypes, including cardiac defects, craniofacial dysmorphisms, and neurocognitive delays (4). Although the origins of these phenotypes are still poorly understood, studies of model organisms show that many of the observed structural and functional defects can indeed be mimicked by targeted introduction of mutations found in RASopathies (5). Hundreds of such mutations have already been identified, and many more are likely to be discovered by the sequencing of affected individuals (6).Importantly, these studies identify new mutations in the very same components that are mutated in cancer and have been extensively studied both in vitro and in vivo (7-9). In particular, multiple new mutations were identified in MEK1, a MAPK kinase (10) and an important target for anticancer therapeutics (11)(12)(13)(14)(15)(16)(17)(18)(19). Because it is commonly believed that cancer mutations would be embryonic lethal when inherited through t...

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

Cited by 47 publications

References 36 publications

Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Efficacy and safety of two doses of Norditropin<sup>®</sup> (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

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