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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

Context

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.

Objective

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.

Methods

This is a multicenter retrospective study.

Results

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.

Conclusions

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.

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Jacques Beltrand, Najiba Lahlou, Tifenn Le Charpentier, Guy Sebag, Sofia Leka, Michel Polak, Nadia Tubiana-Rufi, Didier Lacombe, Marc de Kerdanet, Frederic Huet, Jean-Jacques Robert, Didier Chevenne, Pierre Gressens, and Claire Lévy-Marchal

Context

Recently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli–Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients.

Patients and methods

A 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-d-aspartate) and the patient serum, with or without leptin.

Results

A negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin.

Conclusion

Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

Free access

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.

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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.