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Looking for the skeleton in the closet—rare genetic diagnoses in patients with diabetes and skeletal manifestations

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Abstract

Aims

The precision medicine approach of tailoring treatment to the individual characteristics of each patient has been a great success in monogenic diabetes subtypes, highlighting the importance of accurate clinical and genetic diagnoses of the type of diabetes. We sought to describe three unique cases of childhood-onset diabetes in whom skeletal manifestations led to the revelation of a rare type of diabetes.

Methods 

Case-scenarios and review of the literature.

Results

Case 1: A homozygous mutation in TRMT10A, a tRNA methyltransferase, was identified in a 15-year-old boy with new-onset diabetes, developmental delay, microcephaly, dysmorphism, short stature and central obesity. The progressive apoptosis of pancreatic beta cells required insulin replacement therapy, with increased demand due to an unfavorable body composition. Case 2: Congenital generalized lipodystrophy type 1 was suspected in an adolescent male with an acromegaloid facial appearance, muscular habitus, and diabetes who presented with a pathological fracture in a cystic bone lesion. A homozygous mutation in AGPAT2, an acyl transferase which mediates the formation of phospholipid precursors, was identified. Leptin replacement therapy initiation resulted in a remarkable improvement in clinical parameters. Case 3: A 12-year-old boy with progressive lower limb weakness and pain was diagnosed with diabetic ketoacidosis. Diffuse diaphyseal osteosclerosis compatible with the diagnosis of Camurati-Engelmann disease and a heterozygous mutation in TGFβ1 were identified. Preservation of euglycemia by insulin replacement relieved pain, suggesting that the diabetic milieu may have augmented TGFβ1 overexpression.

Conclusion

Unraveling the precise genetic cause for the clinical manifestations led to the prediction of phenotypic manifestations, and enhanced the clinical outcomes.

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All data are provided in the manuscript.

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Acknowledgements

The authors wish to thank the subjects and their parents who participated in this study. The study was supported in part by the Morris Kahn family foundation, ISF Grant 2034/18 (to OSB) and the National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space. The authors thank Esther Eshkol for editorial assistance.

Funding

None. The study was supported in part by the Morris Kahn family foundation, ISF Grant 2034/18 (to OSB) and the National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space.

Author information

Authors and Affiliations

  1. Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, 6423906, Tel Aviv, Israel

    Avivit Brener, Talya Rosenfeld, Efrat Chorna & Yael Lebenthal

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Avivit Brener, Leonid Zeitlin, Yael Wilnai & Yael Lebenthal

  3. Pediatric Orthopedic Department, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Leonid Zeitlin

  4. The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Yael Wilnai

  5. Genetics Institute at Soroka Medical Center and the Morris Kahn Laboratory of Human GeneticsFaculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Ohad S. Birk

  6. The Nutrition & Dietetics Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Talya Rosenfeld

  7. Social Services, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Efrat Chorna

Authors
  1. Avivit Brener
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  2. Leonid Zeitlin
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Contributions

AB and YL Conceptualization, AB, LZ, YW, OSB, TR, EC and YL Data curation, LZ, YW and OSB Investigation, AB Writing—original draft, AB, LZ, YW, OSB, TR, EC and YL Writing—review & editing, All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Avivit Brener.

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The authors declare no conflicts of interest.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki.

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The patients and their parents gave their informed consent to publish their case.

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Brener, A., Zeitlin, L., Wilnai, Y. et al. Looking for the skeleton in the closet—rare genetic diagnoses in patients with diabetes and skeletal manifestations. Acta Diabetol 59, 711–719 (2022). https://doi.org/10.1007/s00592-022-01854-7

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  • DOI: https://doi.org/10.1007/s00592-022-01854-7

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