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Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children

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Abstract

Background

Short stature (SS) is defined as height more than 2 standard deviations below the mean for age and sex. Hypothyroidism, celiac disease, growth hormone deficiency, hormonal abnormalities, and genetic conditions are among its causes. A wide range of conditions often due to largely unknown genetic variants can elude conventional diagnostic workup.

Aim

We used next-generation sequencing (NGS) to better understand the etiology of SS in a cohort of Italian children.

Patients and methods

The study sample was 125 children with SS of unknown origin referred to our Institute between 2015 and 2021. All had undergone complete auxological and hormonal investigations to exclude common causes of SS. Genetic analysis was performed using a NGS panel of 104 genes. Clinical data were reviewed to clarify the pathogenicity of the variants detected.

Results

In this cohort, 43 potentially causing variants were identified in 38 children. A syndromic genetic condition was diagnosed in 7: Noonan syndrome in 3, Leri–Weill syndrome in 3, and hypochondroplasia in 1. Moreover, 8 benign variants and other 37 like benign variants were found. In 88 children, 179 variants of uncertain significance (VUS) were identified. No variant was found in 16 children.

Conclusion

Genetic analysis is a useful tool in the diagnostic workup of patients with SS, in adapting management and treatment, and in identifying syndromes with mild atypical clinical features. The role of VUS should not be underestimated, particularly when multiple VUS with possible mutual worsening effects are present in the same child.

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Data availability

The data is available in our university hospital, without difficulty. We have tried to report as much data as possible in the tables and supplementary files.

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Funding

This 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. Pediatric Division, Department of Pediatrics, University Hospital of Verona (Full Member of European Reference Network Endo-ERN), Verona, Italy

    P. Cavarzere, A. Pietrobelli, S. Munari, R. Gaudino, M. Arrigoni, G. Piacentini & F. Antoniazzi

  2. Department Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric Clinic, University of Verona, Verona, Italy

    A. Pietrobelli, A. Gandini, R. Gaudino, G. Piacentini & F. Antoniazzi

  3. Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    A. M. Baffico, M. Maffei & D. Coviello

  4. Laboratory Unit, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    A. Guzzo

  5. Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Regional Center for the Diagnosis and Treatment of Children and Adolescents with Rare Skeletal Disorders, Pediatric Clinic, University of Verona, Verona, Italy

    F. Antoniazzi

  6. Department of Pediatrics, Child and Mother’s Hospital, Piazzale Stefani 1, 37126, Verona, Italy

    P. Cavarzere

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  1. P. Cavarzere
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Contributions

All the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Moreover, all the authors read and approved the final manuscript. In particular: PC conceived of the study, contributed to the preparation and critical review of the manuscript; SM, MA and RG wrote the manuscript; AG, AMB, MM, DC and AG contributed in the genetic analysis; FA, GP and AP conceived the study and participated in its coordination.

Corresponding author

Correspondence to P. Cavarzere.

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Conflict of interest

The authors declare no conflict of interest that could compromise the impartiality of the research reported and that no financial support was requested for this study.

Research involving human participants and/or animals

The Institutional Ethics Committee of the provinces of Verona and Rovigo, Italy, took note of the retrospective design of the study and approved the results for publication.

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Written informed consent was obtained from the parents or the guardians of each patient.

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Cavarzere, P., Pietrobelli, A., Gandini, A. et al. Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children. J Endocrinol Invest 47, 1237–1250 (2024). https://doi.org/10.1007/s40618-023-02243-9

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