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Clinical Phenotype and Bone Biopsy Characteristics in a Child with Proteus Syndrome

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Abstract

Proteus syndrome is a rare genetic disorder, which is characterized by progressive, segmental, or patchy overgrowth of diverse tissues of all germ layers, including the skeleton. Here, we present a 9-year-old girl with a somatic-activating mutation (c.49G > A; p.Glu17Lys) in AKT1 gene in a mosaic status typical for Proteus syndrome. She presented with hemihypertrophy of the right lower limb and a “moccasin” lesion among others. A transiliac bone biopsy was analyzed for bone histology/histomorphometry as well as bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) characteristics based on quantitative backscattered electron imaging. Bone histomorphometry revealed highly increased mineralizing surface (Z-score + 2.3) and mineral apposition rate (Z-score + 19.3), no osteoclasts (Z-score − 2.1), and an increased amount of primary bone in the external cortex. BMDD abnormalities included a decreased mode calcium concentration in cancellous bone (Z-score − 1.7) and an increased percentage of highly mineralized cortical bone area (Z-score + 2.4) compared to reference. OLS characteristics showed several differences compared to reference data; among them, there were the highly increased OLS-porosity, OLS-area, and OLS-perimeter on the external cortex (Z-scores + 6.8, + 4.4 and 5.4, respectively). Our findings suggest that increased bone formation reduced matrix mineralization in cancellous bone while the enhanced amount of primary bone in the external cortex increased the portion of highly mineralized cortical bone and caused OLS-characteristics abnormalities. Our results indicate further that remodeling of primary bone might be disturbed or delayed in agreement with the decreased number of osteoclasts observed in this child with Proteus syndrome.

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Acknowledgements

The authors thank P. Keplinger, S. Lueger, and P. Messmer for technical assistance with sample preparation, light microscopy, and qBEI measurements at the Bone Material Laboratory of the Ludwig Boltzmann Institute of Osteology, Vienna, Austria.

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Authors and Affiliations

  1. Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin Str. 30, 1140, Vienna, Austria

    Ali Al Kaissi, Barbara M. Misof, Stéphane Blouin & Paul Roschger

  2. Department of Pediatric Orthopaedics, Orthopaedic Hospital Speising, Vienna, Austria

    Ali Al Kaissi, Gabriel T. Mindler & Rudolf Ganger

  3. Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria

    Franco Laccone

  4. Center of Pathobiochemistry and Genetics, Institute of Medical Chemistry, Medical University of Vienna, Vienna, Austria

    Susanne G. Kircher

  5. Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, 22110, Jordan

    Mohammad Shboul

  6. Department of Plastic and Reconstructive Surgery, Medical University Graz, Graz, Austria

    Werner Girsch

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  1. Ali Al Kaissi
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Contributions

Study design: AAK, RG; Study conduct: AAK, RG. Data collection: AAK, BMM, FL, SB, PR, SGK, MS, GTM, WG. Data analysis: AAK, BMM, FL, SB, PR. Data interpretation: AAK, BMM, FL, SB, PR. Drafting manuscript: AAK, BMM, SB. Revising manuscript content: AAK, BMM, FL, SB, PR, SGK, MS, GTM, WG, RG. Approving final version of the manuscript: AAK, BMM, FL, SB, PR, SGK, MS, GTM, WG, RG. AAK and BMM take responsibility for the integrity of the clinical and biopsy data analysis, respectively.

Corresponding author

Correspondence to Barbara M. Misof.

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Disclosures

AAK, BMM, FL, SB, PR, SGK, MS, GTM, and WG state that they have no conflicts of interest. RG served as a consultant for Smith & Nephew and NuVasive Company, USA. This work was supported by the AUVA (Austrian Social Insurance for Occupational Risk) and the OEGK (Austrian Social Health Insurance Fund).

Informed Consent

Informed consent to participate and to publish was obtained from the patients’ parent.

Research Involving Human and/or Animal Participants

This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and was approved by the Institutional Ethics Committee (Ethikkommission der Wiener Krankenhäuser der Vinzenz Gruppe, Approval number EK 54/2020).

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Al Kaissi, A., Misof, B.M., Laccone, F. et al. Clinical Phenotype and Bone Biopsy Characteristics in a Child with Proteus Syndrome. Calcif Tissue Int 109, 586–595 (2021). https://doi.org/10.1007/s00223-021-00862-z

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