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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

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.