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Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis

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Abstract

Introduction

Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations).

Methods

We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5.

Results

We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median – 2.2 SDS vs. – 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median – 2.8 SDS vs. – 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1–2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6–5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5–3.1 for rhGH-treated iPPSD5 (n = 2).

Conclusion

Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are very grateful to the Acrodysostosis Support & Research Group, the patients, and their families for their important contribution to the study.

Funding

This work was partially supported by the following grants: Instituto de Salud Carlos III (ISCIIII) of the Ministry of Economy and Competitiveness (Spain) (to GPdN and AP: PI20/00950), European Regional Development Fund, a grant from the Department of Health of the Basque Government (GV2021/111056 to GPdN), the 2019 Research Unit Grant from European Society for Paediatric Endocrinology (ESPE) (to GdPN, GM, and AL), the Ricerca Corrente Funds from the Italian Ministry of Health to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (GM)), the AP-HP recurrent funds from the rare disease plan (to A.L. and DA.E.), the RaDiCo PIA « ANR» IO-COHO-03 grant (to A.L.), and the Progetti di Ricerca di Interesse Nazionale (PRIN) grant to GM (2020FYCCE3).

Author information

Authors and Affiliations

  1. AP-HP, Department of Endocrinology and Diabetology for Children and Department of Adolescent Medicine, Bicêtre Paris-Saclay University Hospital, 78 Rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France

    D.-A. Ertl, A. Rothenbuhler, C. Audrain, J. Berkenou & A. Linglart

  2. AP-HP, Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR and Platform of Expertise for Rare Diseases Paris-Saclay, Bicêtre Paris-Saclay Hospital, 78 Rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France

    D.-A. Ertl, A. Rothenbuhler, C. Audrain, J. Berkenou & A. Linglart

  3. University Paris Saclay, Le Kremlin-Bicêtre, France

    D.-A. Ertl, A. Rothenbuhler & A. Linglart

  4. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    D.-A. Ertl

  5. Reference Center for Rare Bone and Growth Disorders: Vienna Bone and Growth Center (ERN-BOND), Vienna, Austria

    D.-A. Ertl

  6. Endocrinology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, University of Milan, Milan, Italy

    G. Mantovani, F. M. Elli & A. Pagnano

  7. Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, Spain

    G. P. de Nanclares & A. Pereda

  8. Pediatrics Service, Dysmorphology Consultation, Dr Peset University Hospital, Valencia, Spain

    A. Sanchis

  9. Department of Clinical and Molecular Genetics, Vall d’Hebron Barcelona Campus Hospital, Barcelona, Spain

    A. M. Cueto-Gonzalez

  10. Medicine Genetics Group, Vall d’Hebron Barcelona Campus Hospital, Vall d’Hebron Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, Spain

    A. M. Cueto-Gonzalez

  11. European Reference Network Craniofacial Anomalies and ENT Disorders (ERN CRANIO and ERN ITHACA), Barcelona, Spain

    A. M. Cueto-Gonzalez

  12. Section of Pediatric Endocrinology, Navarra Hospital Complex, Pamplona, Navarra, Spain

    S. Berrade

  13. Pediatric Endocrinology Unit, CIBERER, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    M. C. León

  14. Acrodysostosis Support and Research, Reg 1182818, London, UK

    N. Knight & K. Dolman

  15. Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria

    A. Gleiss

  16. Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación la Princesa, Madrid, Spain

    J. Argente

  17. Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain

    J. Argente

  18. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

    J. Argente

  19. IMDEA Food Institute, Madrid, Spain

    J. Argente

Authors
  1. D.-A. Ertl
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  2. G. Mantovani
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  3. G. P. de Nanclares
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  4. F. M. Elli
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  18. A. Linglart
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Corresponding author

Correspondence to D.-A. Ertl.

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Conflict of interest

DAE reports receiving travel grants and honoraria from Novo Nordisk, Pfizer and Merck Serono. AL reports receiving research grant support and honoraria from Novo Nordisk, Sandoz, Pfizer, and Merck Serono. All disclosures mentioned are unrelated to this research project. The other authors have no conflicts of interest.

Ethical approval

Participants were selected initially from France, Italy and Spain. For the French participants, the need for written consent was waived, according to national laws. The other centers received approval from their local ethics committees for the collection and sharing of patient data in a pseudonymized manner. The original cohort was extended with the help of the Acrodysostosis Support and Research Patients’ Group, UK, which provided pseudonymized data from families consenting to participate in the study. 

Informed consent

In accordance with the Jardé law in France, as the study was approved by the French Data Protection Authority (CNIL), the need for written consent was waived. Patients and/or their parents/legal guardians were informed verbally of the objectives and procedures of the study and their consent was obtained. They have the right to refuse to participate or to withdraw at any time by writing to http://recherche.aphp.fr/eds/droit-opposition. All other centers were approved by local ethics committees for the collection of data on the patients, which were transferred and analyzed in a pseudonymized manner.

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Ertl, DA., Mantovani, G., de Nanclares, G.P. et al. Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis. J Endocrinol Invest 46, 1673–1684 (2023). https://doi.org/10.1007/s40618-023-02026-2

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