You are here

Article Text

Article menu

Download PDFPDF

Genotype-phenotype correlations
Original article
‘Metaphyseal dysplasia without hypotrichosis’ can present with late-onset extraskeletal manifestations
  1. Svetlana Vakkilainen1,2,
  2. Alice Costantini3,4,
  3. Mervi Taskinen1,
  4. Ulla Wartiovaara-Kautto5,6,
  5. Outi Mäkitie7,8
  1. 1 New Children's Hospital, Pediatric Research Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
  2. 2 Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
  3. 3 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  4. 4 Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
  5. 5 Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland
  6. 6 Applied Tumor Genomics / Research Programs Unit, University of Helsinki, Helsinki, Finland
  7. 7 New Children's Hospital, Pediatric Research Center and Institute of Genetics, University of Helsinki and HUS Helsinki University Hospital and Folkhälsan Research Center, Helsinki, Finland
  8. 8 Department of Molecular Medicine and Surgery and Center for Molecular Medicine and Department of Clinical Genetics, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Dr Svetlana Vakkilainen, New Children's Hospital, Pediatric Research Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00100, Finland; svetlana.vakkilainen{at}hus.fi

Abstract

Background Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extraskeletal manifestations. MDWH is caused by RMRP mutations, but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterised by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown.

Objective We diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair. Based on this observation, we hypothesised that MDWH may, similar to CHH, associate with immune deficiency and malignancy.

Methods We collected clinical and laboratory data for a cohort of 80 patients with RMRP mutations followed for over 30 years and analysed outcome data for those with features consistent with MDWH.

Results In our cohort, we identified 10 patients with skeletal but no extraskeletal features during preschool age. Eight of these patients developed malignancy or clinically significant immunodeficiency during follow-up. Two of them died during chemotherapy for malignancy. At the time of the first extraskeletal manifestation, patients were school aged, 20, 43 and 50 years old. Laboratory signs of immunodeficiency (impaired lymphocyte proliferative responses) were demonstrated in four patients before the onset of symptoms. The patient outside this cohort, who had RMRP mutations, skeletal dysplasia, normal hair and severe agranulocytosis at 18 years of age, underwent haematopoietic stem cell transplantation.

Conclusions MDWH can present with severe late-onset extraskeletal manifestations and thus should be reclassified and managed as CHH.

  • agranulocytosis
  • cartilage-hair hypoplasia
  • immunodeficiency
  • malignancy
  • rmrp

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2019-106131

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • Contributors SV and OM planned the research. SV collected and analysed the data and drafted the manuscript. AC performed the genetic analysis. SV, AC, MT, UW-K and OM edited and finalised the manuscript and approved the final version.

    • Funding The study was funded by the Sigrid Jusélius Foundation (OM), the Academy of Finland (OM), the Folkhälsan Research Foundation (OM), the Novo Nordisk Foundation (OM), the Helsinki University Hospital Research Funds (MT and OM), the Swedish Childhood Cancer Foundation (OM), the Foundation for Pediatric Research (MT and OM) and the Doctoral School in Health Sciences at the University of Helsinki (SV).

    • Competing interests UW-K declares consultancy to Pfizer, Amgen, Novartis and Sanofi. OM declares consultancy to Kyowa Kirin, Alexion and Sandoz.

    • Patient consent for publication Obtained.

    • Ethics approval This study is part of our research programme on skeletal dysplasias in Finland, approved by the Institutional Research Ethics Committee at Helsinki University Hospital, Finland.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.