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Catie Cessans, Virginie Ehlinger, Catherine Arnaud, Armelle Yart, Yline Capri, Pascal Barat, Benoit Cammas, Didier Lacombe, Régis Coutant, Albert David, Sabine Baron, Jacques Weill, Bruno Leheup, Marc Nicolino, Jean-Pierre Salles, Alain Verloes, Maithé Tauber, Hélène Cavé, and Thomas Edouard

Background

Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.

Objective

The goal of this study was to compare growth parameters according to genotype in patients with NS.

Subjects and methods

The study population included 420 patients (176 females and 244 males) harboring mutations in the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines-associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.

Results

Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated.

Conclusion

Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.

Free access

Sophie Moniez, Catherine Pienkowski, Benoit Lepage, Safouane Hamdi, Myriam Daudin, Isabelle Oliver, Béatrice Jouret, Audrey Cartault, Gwenaelle Diene, Alain Verloes, Hélène Cavé, Jean-Pierre Salles, Maithé Tauber, Armelle Yart, and Thomas Edouard

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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Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Helene Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-maciejewski, Florence Compain, Regis Coutant, Jessica Amsellem-jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Soskin Sylvie, Aurélie Berot, Naud-saudreau Catherine, Jean-pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54 vs. 15%, p = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of mutated infants) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, ‘cell proliferation group’; 69% of mutated children and adolescents). Although serum calcium levels did not differ between the 2 groups (p = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ (p = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.