Professor Leo Dunkel

Profile

Professor Leo Dunkel graduated in Medicine in 1981 at the University of Helsinki, Finland and completed his residency in Paediatrics and Paediatric Endocrinology at the Hospital for Children and Adolescents, University of Helsinki. After his residency, he undertook postdoctoral training in the Division of Reproductive Biology at Stanford University. He worked at the University of Kuopio, Finland, as Chair of Paediatrics in the Department of Clinical Medicine, before moving to the Centre for Endocrinology at the William Harvey Research Institute in 2011.

Professor Dunkel was the Founding member and first Chairman of the Finnish Society for Paediatric Endocrinology (1999) and has been an active member of the European Society for Paediatric Endocrinology (Member from 1988), including as a Council Member (2000-2004) and Program Organising Committee Member (2007-2012). Professor Dunkel has also served on the Committee for Scientific Education, Faculty of Medicine, University of Helsinki (1998-2001) and University of Kuopio (2004-2011) and on the Editorial Boards of several scientific journals. He currently serves on the Editorial Board of the Journal of Clinical Endocrinology and Metabolism.

Research

Collaborators and alumni
Prof Leonardo Guasti; Dr Sasha Howard (Clinical Reader)

Dr Muriel Meso; Dr Harsini Katugampola; Dr Jayna Mistry; Dr Alessandra Mancini; Dr Tansit Saengkaew

Summary 

Paediatric Endocrinology Research Group
Professor Dunkel has a long-standing interest in the area of growth and puberty. In the past 10 years, he has focused on the regulation of linear growth. These studies have culminated in a conceptually new paradigm: inhibiting the biological action of oestrogen could provide an efficacious therapy for treating various growth disorders. Indeed, the growth promoting potential of a third-generation aromatase inhibitor is currently being investigated in two placebo-controlled clinical trials.

Professor Dunkel is also using genetic tools to establish the causes of X in his well-characterized cohort So far, these studies have established that a previously uncharacterised gene (IGSF10) promotes the growth and differentiation of gonadotropin-releasing hormone (GnRH) neurons, an important discovery because it implicates involvement of a previously unsuspected biological pathway in the control of pubertal timing.  He has also accrued good evidence that ISGF10 variants may underlie some cases of hypogonadotrophic hypogonadism (HH), where patients have complete pubertal failure due to GnRH deficiency.

A major focus of Professor Dunkel’s current work is the development of novel cell models to interrogate the genetic factors underlying the timing of sexual maturation through the GnRH neuronal network (see Figures 1 through 3). To this end, his group has generated induced pluripotent stem cell (iPSC) lines to enable study of neuronal growth and GnRH-neuron differentiation in patients with disorders of sexual maturation: self-limited delayed puberty, Kallmann Syndrome (KS) and HH. This platform promises to act as a basis for delineating the processes of neuronal maturation, for example, by genetically manipulating candidate gene expression in patient-generated iPSC lines. It also provides an excellent resource to study the functional effects of variants found in his exome sequencing studies of patients with self-limited delayed puberty.  

Genetics of the timing of puberty

Figure 1. Genetics of the timing of puberty.  The precise genetic causes of the extreme tails of normal puberty are unclear, as is the basis of association of specific gene variants with pubertal timing in the general population (outside of families with GnRH deficiency or self-limited delayed puberty). Understanding the role(s) of gene variants influencing the timing of puberty, both precocious and delayed, is expected to contribute to the understanding of the biological control of human pubertal timing both in disease and in the general population. This knowledge could directly help patients through improved diagnostic ease and facilitate identification of gene-environmental interactions. Based on the observed inheritance pattern, we hypothesize that families with inherited constitutional delay in growth and puberty are enriched for genetic variants that have high-impact on pubertal timing and, that these variants are amenable to discovery using modern molecular genetic tools. Recently, we have discovered evidence that such high impact variants may influence the timing of puberty, significantly delaying the onset of puberty in a subset of families.

Figure 2. Overlap between genetic regulation of the timing of puberty in the general population and in patients. Orange, examples of gene signals identified by genome-wide association studies (GWAS) as regulating the timing of puberty in the general population. Genes associated with conditions of gonadotropin releasing hormone (GnRH) deficiency, such as idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS), and (in blue) self-limited delayed puberty.

 

Figure 3. Working model of how IGSF10 mutations delay puberty. Reduced IGSF10 expression during embryogenesis in the corridor of nasal mesenchyme cells of the vomeronasal organ (VNO) leading to the olfactory bulbs delays the migration of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamus. This reduction manifests in adolescence as a phenotype of delayed puberty due to abnormalities of the GnRH neuronal network.

Key Publications

Full list of publications

1. Cassatella D, Howard S, Acierno J, Xu C, Papadakis G, Santoni FA, Dwyer AA, Santini S, Sykiotis G, Chambion C, Meylan J, Marino L, Favre L, Li J, Liu X, Zhang JG, Bouloux P, De Geyter C, De Paepe A, Dhillo WS, Ferrara JM, Hauschild M, Lang-Muritano M, Lemke J, Flück CE, Nemeth A, Phan-Hug F, Pignatelli D, Popovic V, Pekic S, Quinton R, Szinnai G, l'Allemand D, Konrad D, Sharif S, Iyidir ÖT, Stevenson BJ, Yang H, Dunkel L, Pitteloud N. Congenital Hypogonadotropic Hypogonadism and Constitutional Delay of Growth and Puberty Have Distinct Genetic Architectures. Eur J Endocrinol. 2018 Feb 1. pii: EJE-17-0568. doi: 10.1530/EJE-17-0568. [Epub ahead of print] PubMed PMID: 29419413.
2. Howard SR, Guasti L, Poliandri A, David A, Cabrera CP, Barnes MR, Wehkalampi K, O'Rahilly S, Aiken CE, Coll AP, Ma M, Rimmington D, Yeo GSH, Dunkel L. Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty. J Clin Endocrinol Metab. 2018 Feb 1;103(2):649-659. doi: 10.1210/jc.2017-02147. PubMed PMID: 29161441.
3. Howard SR, Dunkel L. The Genetic Basis of Delayed Puberty. Neuroendocrinology. 2017 Sep 18. doi: 10.1159/000481569. [Epub ahead of print] PubMed PMID: 28926843. 
4. Poliandri A, Miller D, Howard S, Nobles M, Ruiz-Babot G, Harmer S, Tinker A, McKay T, Guasti L, Dunkel L. Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells. Mol Cell Endocrinol. 2017 May 15;447:12-22. doi: 10.1016/j.mce.2017.02.030. Epub 2017 Feb 21. PubMed PMID: 28232089. 
5. Howard SR, Guasti L, Ruiz-Babot G, Mancini A, David A, Storr HL, Metherell LA, Sternberg MJ, Cabrera CP, Warren HR, Barnes MR, Quinton R, de Roux N, Young J, Guiochon-Mantel A, Wehkalampi K, André V, Gothilf Y, Cariboni A, Dunkel L. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Mol Med. 2016 Jun 1;8(6):626-42. doi: 10.15252/emmm.201606250. Print 2016 Jun. PubMed PMID: 27137492; PubMed Central PMCID: PMC4888853. 
6. Scherdel P, Dunkel L, van Dommelen P, Goulet O, Salaün JF, Brauner R, Heude B, Chalumeau M. Growth monitoring as an early detection tool: a systematic review. Lancet Diabetes Endocrinol. 2016 May;4(5):447-56. doi: 10.1016/S2213-8587(15)00392-7. Epub 2016 Jan 15. Review. PubMed PMID: 26777129. 
7. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015 Sep;11(9):547-64. doi: 10.1038/nrendo.2015.112. Epub 2015 Jul 21. Review. PubMed PMID: 26194704. 
8. Saari A, Harju S, Mäkitie O, Saha MT, Dunkel L, Sankilampi U. Systematic growth monitoring for the early detection of celiac disease in children. JAMA Pediatr. 2015 Mar;169(3):e1525. doi: 10.1001/jamapediatrics.2015.25. Epub 2015 Mar 2. PubMed PMID: 25730696. 
9. Guasti L, Silvennoinen S, Bulstrode NW, Ferretti P, Sankilampi U, Dunkel L. Elevated FGF21 leads to attenuated postnatal linear growth in preterm infants through GH resistance in chondrocytes. J Clin Endocrinol Metab. 2014 Nov;99(11):E2198-206. doi: 10.1210/jc.2014-1566. Epub 2014 Aug 19. PubMed PMID: 25137423.
10. Sankilampi U, Saari A, Laine T, Miettinen PJ, Dunkel L. Use of electronic health records for automated screening of growth disorders in primary care. JAMA. 2013 Sep 11;310(10):1071-2. doi: 10.1001/jama.2013.218793. PubMed PMID: 24026604.
11. Sankilampi, U., Saari, A., Laine, T., Miettinen, P.J., and Dunkel, L. 2013. Use of electronic health records for automated screening of growth disorders in primary care. JAMA : the Journal of the American Medical Association 310:1071-1072.
12. Palmert , M., Dunkel, L. 2012. Delayed puberty. New England Journal of Medicine. 366:40-50.
13. Saari, A., Sankilampi, U., Hannila, M.L., Saha, M.T., Makitie, O., and Dunkel, L. 2012. Screening of Turner Syndrome with Novel Auxological Criteria Facilitates Early Diagnosis. The Journal of clinical endocrinology and metabolism. 10.1210/jc.2012-1739
14. Kuiri-Hänninen T, Kallio S, Seuri R, Tyrväinen E, Liakka A, Tapanainen J, Sankilampi U,  Dunkel L. 2011 Postnatal Developmental Changes in the Pituitary-Ovarian Axis in Preterm and Term Infant Girls The Journal of clinical endocrinology and metabolism 96: 3432-3439. 10.1097/OGX.0b013e318254713b 
15. Kuiri-Hanninen, T., Seuri, R., Tyrvainen, E., Turpeinen, U., Hamalainen, E., Stenman, U.H., Dunkel, L., and Sankilampi, U. 2011. Increased activity of the hypothalamic-pituitary-testicular axis in infancy results in increased androgen action in premature boys. The Journal of clinical endocrinology and metabolism 96:98-105. 
16. Wehkalampi, K., Hovi, P., Dunkel, L., Strang-Karlsson, S., Jarvenpaa, A.L., Eriksson, J.G., Andersson, S., and Kajantie, E. 2011. Advanced pubertal growth spurt in subjects born preterm: the Helsinki study of very low birth weight adults. The Journal of clinical endocrinology and metabolism 96:525-533. 10.1210/jc.2010-1523 
17. Hero, M., Toiviainen-Salo, S., Wickman, S., Makitie, O., and Dunkel, L. 2010. Vertebral morphology in aromatase inhibitor-treated males with idiopathic short stature or constitutional delay of puberty. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 25:1536-1543. 
18. Wehkalampi, K., Widen, E., Laine, T., Palotie, A., and Dunkel, L. 2008. Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care. The Journal of clinical endocrinology and metabolism 93:723-728. 10.1210/jc.2007-1786 
19. Hero, M., Norjavaara, E., and Dunkel, L. 2005. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. The Journal of clinical endocrinology and metabolism 90:6396-6402.
20. Wickman, S., Sipila, I., Ankarberg-Lindgren, C., Norjavaara, E., and Dunkel, L. 2001. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 357:1743-1748.

Collaborators

Internal
Dr. Helen Storr (Endocrinology); Professor Louise Metherell (Endocrinology)

External
Prof. Nelly Pitteloud (Lausanne, Switzerland); Prof. Mark Palmert (Toronto, Canada); Yee-Ming Chan (Boston, USA); Raja Brauner (Paris, France); Anders Juul (Copenhagen, Denmark); Romina Grinspon and Rodolfo Rey (Buenos Aires, Argentina); Alexander Jorge and Ana Claudia (São Paolo, Brazil); Verónica Mericq and Paulina Merino; (Santiago, Chile); Vincent Prevot (Lille France); Jaques Young (Paris, France); Anna Cariboni (Milan, Italy)