Fondation Ipsen Young Investigator Award awarded during ICE 2018

Fondation Ipsen Young Investigator Award awarded during ICE 2018

During the International Congress in Endocrinology, ICE 2018 in Cape Town, South Africa,  Dr. Larissa Gomez (Brazil) was awarded with the Fondation Ipsen Young Investigator Award for the best young investigator in Endocrinology. She received this Award for her abstract “Untreated familial central precocious puberty followed by PCOS and type 2 DM caused by a novel DLK1 mutation”, which was considered the best submitted abstract by a young investigator by the ICE Program Organising Committee.

The award was presented to Larissa by Dr. Xavier Bertagna (France).

Following the award ceremony, Dr Gomes presented her talk.

Untreated familial central precocious puberty followed by PCOS and type 2 DM caused by a novel DLK1 mutation

L Gomes1, R Crespo1, G Maciel2, Prof A Jorge1, T Rocha1, L Montenegro1, E Baracat2, T Bachega1, AC Latronico1, B Mendonça1

1Division of Endocrinology and Metabolism, Hospital das Clínicas, University of São Paulo School of Medicine, Sao Paulo, Brazil, 2Department of Gynecology & Obstetrics, Hospital das Clínicas, University of São Paulo School of Medicine, Sao Paulo, Brazil

Background: The DLK1 gene has been pointed out as a genetic cause of familial central precocious puberty (CPP). DLK1 is expressed in mouse hypothalamus, which is key region involved in puberty regulation. DLK1 encodes a transmembrane protein that regulates several cell types differentiation, including adipocytes.

Methods: We report two Brazilian sisters, patient 1A (Pt1A) 34 years and patient 1B (Pt1B) 24 years of age. Both presented telarche at 5 years and menarche at 7 years, confirming CPP, without specific treatment at that time. They evolved with oligomenorrhea, hirsutism, infertility (PCOS phenotype) and overweight (Pt1A and Pt1B BMIs are 29.2 and 27.2, respectively). Pt1A had the diagnosis of type 2 diabetes at 27 years and Pt1B at 16 years. Their mother reported her age of menarche as 14 years and age of diabetes diagnosis as 45 years. Whole-exome sequencing of the two siblings and the mother were performed.

Results: Exome sequencing revealed a novel frameshift variant in the exon 5 of DLK1, c.593delC, p.A198fs, in both affected sisters. This variant was absent in the genome database as gnomAD, and the Brazilian database – ABrOM. The variant is located in the calcium-binding EGFlike domain, crucial domain for numerous protein-protein interactions.
The variant segregated with the disease: was absent in the mother and confirmed in the father by Sanger sequencing. This inheritance pattern is consistent with DLK1 paternally expressed imprinted gene.

Conclusion: We have identified a new DLK1 genetic variant associated with familial CPP, with possible impact on adipogenesis and glucose metabolism.