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

Avivit Brener*, Leonid Zeitlin, Yael Wilnai, Ohad S. Birk, Talya Rosenfeld, Efrat Chorna, Yael Lebenthal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Pages (from-to)711-719
Number of pages9
JournalActa Diabetologica
Issue number5
StatePublished - May 2022


FundersFunder number
Morris Kahn family foundation
National Knowledge Center for Rare/Orphan Diseases of the Israel Ministry of Science, Technology and Space
Israel Science Foundation2034/18


    • AGPAT2
    • Body composition
    • Dysmorphic features
    • Lipodystrophy
    • TGFβ1
    • TRMT10A


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