Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Short stature in PRMT7 Mutations: first evidence of response to growth hormone treatment

European Journal of Human Genetics volume 31, pages 195–201 (2023)Cite this article

Subjects

Abstract

Protein arginine methyltransferase 7 (PRMT7) pathogenetic variants have been associated with the human disorder of Short Stature, Brachydactyly, Intellectual Developmental Disability and Seizures syndrome (SBIDDS). Only 15 cases have been described in the literature. Here we report two female dizygotic twins with novel compound heterozygous deleterious variants of PRMT7 and describe the associated endocrine manifestations and short-term response to recombinant growth hormone (rGH) treatment. They were born at 36 + 3 weeks from a dichorionic diamniotic twin pregnancy. Twin A was appropriate for gestational age while Twin B was small for gestational age. Whole exome sequencing analyses showed the same novel compound heterozygous genetic defects in the PRMT7 gene (c.1220 G > A of maternal origin; c.1323 + 2 T > G of paternal origin, Fig. 1). Due to severe short stature and growth impairment, at six years of age, endocrine investigations were performed to rule out growth hormone (GH) deficiency, and revealed GH deficiency (GHD) in Twin A and an appropriate GH response in Twin B. Therefore, both started rGH, albeit at different dosages according to the underlying diagnosis. Both showed a satisfactory short-term response to treatment with height gain (∆HT) of +0.52 SDS (Twin A) and +0.88 SDS (Twin B) during the first year. In conclusion, our findings expand the knowledge about the endocrine manifestations associated with PRMT7 pathogenetic variants, including GH deficiency and rGH response. Further studies are needed to investigate long-term outcomes and establish whether PRMT7 genetic defects can be included among syndromic short stature treatable with rGH.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1
Fig. 2: Growth Curves according to Cacciari Growth Charts.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, et al. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015;47:1363–9.

    Article  CAS  Google Scholar 

  2. Kernohan KD, McBride A, Xi Y, Martin N, Schwartzentruber J, Dyment DA, et al. Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly. Clin Genet. 2017;91:708–16.

    Article  CAS  Google Scholar 

  3. Agolini E, Dentici ML, Bellacchio E, Alesi V, Radio FC, Torella A, et al. Expanding the clinical and molecular spectrum of PRMT7 mutations: Three additional patients and review. Clin Genet. 2018;93:675–81.

    Article  CAS  Google Scholar 

  4. Valenzuela I, Segura-Puimedon M, Rodríguez-Santiago B, Fernández-Alvarez P, Vendrell T, Armengol L, et al. Further delineation of the phenotype caused by loss of function mutations in PRMT7. Eur J Med Genet. 2019;62:182–5.

    Article  Google Scholar 

  5. Birnbaum R, Yosha-Orpaz N, Yanoov-Sharav M, Kidron D, Gur H, Yosovich K, et al. Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations. Am J Med Genet A 2019;179:78–84.

    Article  CAS  Google Scholar 

  6. Poquérusse J, Whitford W, Taylor J, Alburaiky S, Snell RG, Lehnert K, et al. Novel PRMT7 mutation in a rare case of dysmorphism and intellectual disability. J Hum Genet. 2022;67:19–26.

    Article  Google Scholar 

  7. Bertino E, Spada E, Occhi L, Coscia A, Giuliani F, Gagliardi L, et al. Neonatal Anthropometric Charts: The Italian neonatal study compared with other European studies. J Pediatr Gastroenterol Nutr. 2010;51:353–61.

    Article  Google Scholar 

  8. Growth Calculator 4. [Online] http://www.weboriented.it/gh4/.

  9. Tanner JM. Assessment of Skeletal Maturity and Prediction of Adult Height (TW2 Method). 2. Academic Press; 1983.

    Google Scholar 

  10. Linglart A, Levine MA, Jüppner H. Pseudohypoparathyroidism. Endocrinol Metab Clin North Am. 2018;47:865–88.

    Article  Google Scholar 

  11. Mantovani G, de Sanctis L, Barbieri AM, Elli FM, Bollati V, Vaira V, et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab. 2010;95:651–8.

    Article  CAS  Google Scholar 

  12. Linglart A, Maupetit-Méhouas S, Silve C. GNAS -Related Loss-of-Function Disorders and the Role of Imprinting. Horm Res Paediatr. 2013;79:119–29.

    Article  CAS  Google Scholar 

  13. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007;92:804–10.

    Article  CAS  Google Scholar 

  14. De Ridder MA, Stijnen T, Hokken-Koelega AC. Prediction of adult height in growth-hormone-treated children with growth hormone deficiency. J Clin Endocrinol Metab. 2007;92:925–31.

    Article  Google Scholar 

  15. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab. 2003;88:3584–90.

    Article  Google Scholar 

  16. Ranke MB, Lindberg A. KIGS International Board. Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab. 2010;95:1229–37.

    Article  CAS  Google Scholar 

  17. Bang P, Ahmed SF, Argente J, Backeljauw P, Bettendorf M, Bona G, et al. Identification and management of poor response to growth-promoting therapy in children with short stature. Clin Endocrinol (Oxf). 2012;77:169–81.

    Article  CAS  Google Scholar 

  18. Kelnar CJ. Growth hormone therapy in noonan syndrome. Horm Res. 2000;53:77–81.

    CAS  Google Scholar 

  19. Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, et al. Treatment of short stature in aggrecan deficient patients with recombinant human growth hormone: one-year response. J Clin Endocrinol Metab. 2022;107:e2103–9.

    Article  Google Scholar 

  20. Savage MO, Burren CP, Rosenfeld RG. The continuum of growth hormone–IGF-I axis defects causing shortstature: diagnostic and therapeutic challenges. Clin Endocrinol (Oxf). 2010;72:721–8.

    Article  CAS  Google Scholar 

  21. Ozono K, Ogata T, Horikawa R, Matsubara Y, Ogawa Y, Nishijima K. Efficacy and safety of two doses of Norditropin((R)) (somatropin) in short stature due to Noonan syndrome: a 2-year randomized, double-blind, multicenter trial in Japanese patients. Endocr J. 2018;65:159–74.

    Article  Google Scholar 

  22. Dahlgren J, Albertsson-Wikland K. GH responsiveness in children with noonan syndrome compared to turner syndrome. Front Endocrinol (Lausanne). 2021;12:737893.

    Article  Google Scholar 

  23. Chatelain P, Colle M, Nako JP, Le Luyer B, Wagner K, Berlier P, et al. Optimization of growth hormone dosing in children born small for gestational age: an open-label, randomized study of children during the fourth year of therapy. Horm Res Paediatr. 2012;77:156–63.

    Article  CAS  Google Scholar 

  24. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. BMJ 2011;342:c7157.

    Article  Google Scholar 

  25. Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, genetics, and therapy of short stature in children: a growth hormone research society international perspective. Horm Res Paediatr. 2019;92:1–14.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The Authors would like to thank the patients and their parents for their kind cooperation. This work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516).

Funding

The research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author information

Authors and Affiliations

  1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

    Giulia Rodari, Francesca Elli, Federico Giacchetti, Eriselda Profka, Maura Arosio, Giovanna Mantovani & Claudia Giavoli

  2. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Giulia Rodari, Maura Arosio, Giovanna Mantovani & Claudia Giavoli

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Medical Genetic Unit, Milan, Italy

    Roberta Villa & Maria Francesca Bedeschi

  4. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Physical Medicine & Rehabilitation Unit, Milan, Italy

    Matteo Porro

  5. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neonatal Intensive Care Unit (NICU), Milan, Italy67University of Milan, Milan, Italy

    Silvana Gangi

  6. Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy

    Maria Iascone

  7. University of Milan, Milan, Italy

    Valentina Collini & Alberta Dall’Antonia

Authors
  1. Giulia Rodari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matteo Porro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvana Gangi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Iascone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesca Elli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Federico Giacchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eriselda Profka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valentina Collini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alberta Dall’Antonia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maura Arosio
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giovanna Mantovani
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria Francesca Bedeschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Claudia Giavoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RG wrote the first draft of the manuscript; MG, AM and GC have revised the text; EF, BMF and GC have critically reviewed the text and provided substantial scientific contributions. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Claudia Giavoli.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rodari, G., Villa, R., Porro, M. et al. Short stature in PRMT7 Mutations: first evidence of response to growth hormone treatment. Eur J Hum Genet 31, 195–201 (2023). https://doi.org/10.1038/s41431-022-01220-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-022-01220-9

Search

Advanced search

Quick links