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
Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.
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.
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.
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.
Laetitia Martinerie, Yves Morel, Claire-Lise Gay, Catherine Pienkowski, Marc de Kerdanet, Sylvie Cabrol, Claudine Lecointre, Regis Coutant, Sabine Baron, Michel Colle, Raja Brauner, Elisabeth Thibaud, Juliane Leger, Claire Nihoul-Fekete, and Claire Bouvattier
Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys.
The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys.
This is a multicenter retrospective study.
Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a ‘classical’ mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment.
In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.
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
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.
Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France.
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).
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.
Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Hélène Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-Maciejewski, Florence Compain, Régis Coutant, Jessica Amsellem-Jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Sylvie Soskin, Aurélie Berot, Catherine Naud-Saudreau, Jean-Pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie
To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.
Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.
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 infants with mutations) 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 children and adolescents with mutations). Although serum calcium levels did not differ between the two 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).
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.