ESPE Abstracts (2019) 92 RFC11.5

IGF-1 Serum Concentrations and Growth in Children with Congenital Leptin Deficiency (CLD) Before and After Replacement Therapy with Metreleptin

Marianna Beghini1,2, Julia von Schnurbein1, Ingrid Körber1, Stephanie Brandt1, Katja Kohlsdorf1, Heike Vollbach1, Belinda Lennerz3, Christian Denzer1, Martin Wabitsch1


1Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany. 2Operative Unit of Endocrinology- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 3Division of Pediatric Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, MA, USA


Background: Leptin, primarily secreted by adipocytes, is a pivotal signal of the body's energy status and exhibits pleiotropic effects. Homozygous mutations in the leptin gene which result in defective synthesis, release or bioactivity, cause intense hyperphagia and early-onset severe obesity, along with multiple metabolic, hormonal, and immunological abnormalities. In vitro and animal model studies suggest that leptin plays a role in linear growth. So far, this has not been fully investigated in humans.

Objective: To evaluate IGF-1 serum levels and growth before and after 12 months of leptin replacement therapy in patients with congenital leptin deficiency (CLD).

Patients and Methods: This case-series contains n=9 patients (6 males) with CLD due to defective production (n=5) or bioinactive leptin (n=4). We retrospectively analysed data regarding age, height-SDS, BMI-SDS, IGF-1-SDS, IGFBP3-SDS, IGF-1/IGFBP3 ratio-SDS at the beginning (T0), after 6 months (T6) and after 12 months (T12) of leptin replacement therapy.

Results: At baseline, mean age was 8.2±5.4 yrs (range: 0.9-14.8 yrs), mean BMI-SDS was +4.1±1.4 (range:2.3-6.0) and IGF-1-SDS as well as IGF-1/IGFBP3 ratio-SDS were negative in all patients (IGF-1-SDS T0:-1.16±0.83, IGF-1/IGFBP3 ratio-SDS T0:-1.10±0.80). Mean IGFBP3-SDS was 0.17±1.36. Leptin replacement resulted in a reduction of BMI-SDS of 1.40±0.81 after 12 months. During leptin replacement therapy, IGF1-SDS increased from T0:-1.16±0.83 to T6:-0.22±1.81 and to T12:+0.26±1.26. We also observed an increase in IGFBP3-SDS and in IGF-1/IGFBP3 ratio-SDS (ΔT0-T12IGFBP3-SDS=+0.67±0.95, ΔT0-T12IGF-1/IGFBP3 ratio-SDS=+1.16±1.81). Mean change in height-SDS under leptin replacement therapy was not significant; however, when we looked at the individual data, we observed that all children younger than 12 yrs (n=5) showed a positive change (0.12-0.64).

Conclusions: Most studies show that obese children have normal or increased IGF-1 levels, and it is known that IGF-1 levels decrease under caloric restriction (Hawkes and Grimberg, Pediatr Endocrinol Rev. 2015;13(2):499-511). Interestingly, we found that IGF-1 serum levels in severely obese CDL children were low at baseline and increased during metreleptin substitution despite reduced caloric intake. We also observed an acceleration of growth in children <12yo. Our findings support the hypothesis that leptin, as a signal of the energy status, promotes IGF-1 production and growth.