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A new DLK1 defect in a family with idiopathic central precocious puberty: elucidation of the male phenotype

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Abstract

Purpose

We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement.

Methods

We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects.

Results

A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8 years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients.

Conclusion

A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

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Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We gratefully thank all the patients, family members and staff from all the units that participated in the study. Preliminary but partial data of this paper have been presented during the 60th annual meeting of the European Society of Pediatric Endocrinology as an e-poster format. The extended results of the preliminary research are contained in this paper, they are original and not published anywhere else.

Funding

This work was supported by a grant (390) funded by “VALERE: VAnviteLli pEr la RicErca” program of University of Campania “L. Vanvitelli”.

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Authors and Affiliations

  1. Department of Child, Women, General and Specialized Surgery, University of Campania, “L. Vanvitelli”, Vico L. De Crecchio n° 2, 80138, Naples, Italy

    S. Palumbo, G. Cirillo, G. Sanchez, F. Aiello, E. Miraglia del Giudice & A. Grandone

  2. University of Trieste, Trieste, Italy

    A. Fachin & F. Baldo

  3. Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy

    M. C. Pellegrin & G. Tornese

  4. Pediatric Endocrine Unit, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    A. Cassio

  5. Pediatric Endocrine Unit, Department of Translational Medical Sciences, University Federico II, Naples, Italy

    M. Salerno

  6. Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    M. Maghnie

  7. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy

    M. Maghnie

  8. Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari A. Moro, Bari, Italy

    M. F. Faienza

  9. Unit of Paediatrics, Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

    M. Wasniewska

  10. Endocrinology Unit, University-Hospital Pediatric Department, Bambino Gesù Children’s Hospital, IRCSS, Rome, Italy

    D. Fintini

  11. Unit of Pediatrics, Department of Maternal and Child Health, Carlo Poma Hospital, ASST-Mantova, Mantua, Italy

    C. Giacomozzi

  12. Pediatric Unit-“M. Bufalini” Hospital - Cesena, Cesena, Italy

    S. Ciccone

Authors
  1. S. Palumbo
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  2. G. Cirillo
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Contributions

AG and GT conceptualized the idea of the manuscript. AG also coordinated the research process and reviewed drafts. SP reviewed the literature and wrote the manuscript. SP, GC, GS performed genetic analysis. RC, LD and RDF wrote adult cases section. Francesca Aiello reviewed and edited drafts for publication. AF, FB, MCP, AC, MS, MM, MFF, MW, DF, CG, SC and EmdelG performed all clinical examination, collected the data and prepared material. All authors read and approved the final manuscript and take full responsibility for it content.

Corresponding author

Correspondence to A. Grandone.

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Conflict of interest

Mariacarolina Salerno is on the Editorial board of Journal of Endocrinology Investigation. All other authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval

This study involving Human Partecipants was approved by the ethics committee of “Luigi Vanvitelli” University (Protocol number 23.26-20200008943) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent to partecipate and to publish

Written informed consent to partecipate to the study was obtained from adult patients and all legal guardians/parents of children participants included in the study and an informed assent was obtained directly from the minors involved. All patients or their legal guardians/parents gave consent to publication of any data resulting from the study.

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Palumbo, S., Cirillo, G., Sanchez, G. et al. A new DLK1 defect in a family with idiopathic central precocious puberty: elucidation of the male phenotype. J Endocrinol Invest 46, 1233–1240 (2023). https://doi.org/10.1007/s40618-022-01997-y

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  • DOI: https://doi.org/10.1007/s40618-022-01997-y

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