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The landscape of pediatric Diamond-Blackfan anemia in Switzerland: genotype and phenotype characteristics

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Abstract

Diamond-Blackfan anemia (DBA) is caused mainly by genetic mutations in large (RPL) or small ribosomal subunit genes (RPS) and presents with macrocytic anemia and congenital malformations. Clinical differences between genotypes are insufficiently understood. The aim of this study was to assess clinical features, treatment strategies, and genotypes in the Swiss pediatric DBA population. We retrospectively reviewed medical charts of pediatric patients with DBA in Switzerland and stratified patients by RPL versus RPS mutations. We report 17 DBA patients in Switzerland who were all genetically investigated. In our cohort, patients showed a wide spectrum of clinical presentations and treatment needs. We found a high proportion of physical malformations (77%) including lower limb (17%) and anorectal (12%) malformations. The two patients with anorectal malformations presented both with antepositioning of the anus needing surgery within the first 15 months of life. One of these patients had sphincteric dysfunction, the other coccygeal agenesis. We found that included patients with an RPL mutation more frequently tended to have physical malformations and a milder anemia compared to patients with an RPS mutation (median hemoglobin at diagnosis 76 g/l versus 22 g/l).

Conclusion: We illustrate the wide clinical and genetic spectrum of DBA in Switzerland. Our findings highlight the need to take this diagnosis into consideration in patients with severe anemia but also in patients with mild anemia where malformations are present. Lower limb and anorectal malformation extend the spectrum of DBA-associated malformations.

What is Known?

• There is a large variation in the phenotype of Diamond-Blackfan Anemia (DBA) and diversity of genetic mutations.

• Malformation of the upper limbs, head and face, heart, and genitourinary system is frequently identified.

What is New?

• Patients with lower limb and anorectal malformations were repetitively found in our cohort enlarging the clinical spectrum of malformations.

• We show two patients of the same family with a DBA-like condition where the same RPL17 variant was identified.

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Data availability

The datasets that where generated within this study will not be publicly available due to concerns for anonymity of patients with Diamond-Blackfan anemia being a rare disease with very few patients. Datasets that support the findings are available from the corresponding author upon reasonable request.

Abbreviations

DBA :

Diamond-Blackfan Anemia

eADA :

erythrocyte adenosine deaminase activity

GATA-1 :

GATA binding protein 1 gene

HbF :

fetal hemoglobin

Hgb:

hemoglobin

HSCT:

hematopoietic stem cell transplantation

IBMFS:

inherited bone marrow failure syndrome

MCV:

mean corpuscular volume

n:

number

RPS / RPL :

small/large ribosomal subunit protein

SGA:

small for gestational age

SPOG:

Swiss Paediatric Oncology Group

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Acknowledgements

We thank the patients and their parents for participation in the study. Special thanks also to the contributing collaborators (Cantonal Hospital Lucerne, Dr. Christian Reimann; University Hospital Geneva, Dr. Veneranda Mattiello; Regional Hospital Bellinzona, Dr. Pierluigi Brazzola; Cantonal Hospital Graubuenden, Dr. Reta Malaer) for their help with data collection.

Funding

Nicolas Waespe was supported by the CANSEARCH Foundation, Geneva, Switzerland.

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Author notes

    Authors and Affiliations

    1. Department of Pediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland

      Nicole Vogel

    2. University Children’s Hospital, Zurich, Switzerland

      Markus Schmugge

    3. Department of Pediatrics, Lausanne University Hospital CHUV, Lausanne, Switzerland

      Raffaele Renella

    4. Childhood Cancer Research Group, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

      Nicolas Waespe

    5. Research Platform for Pediatric Oncology and Hematology (CANSEARCH Research Platform), Faculty of Medicine, University of Geneva, Geneva, Switzerland

      Nicolas Waespe

    6. Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland

      Nicolas Waespe

    7. Hematology/Oncology Department, Pediatric Hospital of Eastern Switzerland, Claudiusstrasse 6, 9006, St. Gallen, Switzerland

      Heinz Hengartner

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    1. Nicole Vogel
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    Consortia

    on behalf of the Swiss Paediatric Oncology Group (SPOG) Hematology Working Group

    Contributions

    Nicole Vogel: conceptualization, methodology, data preparation and curation, writing—all stages, visualization;

    Markus Schmugge: writing—reviewing and editing;

    Raffaele Renella: writing—reviewing and editing;

    Nicolas Waespe: conceptualization, methodology, writing—all stages, equally contributing senior author;

    Heinz Hengartner: supervision, conceptualization, methodology, writing—all stages, equally contributing senior author.

    Corresponding author

    Correspondence to Heinz Hengartner.

    Ethics declarations

    Ethics approval

    This study was performed in line with the principles of the Declaration of Helsinki. Approval number 2018-01793, leading committee: Eastern Switzerland. Date 09.10.2018. Written informed consent was obtained from patients and/or parents.

    Conflict of interest

    The authors declare no competing interests.

    Additional information

    Communicated by Gregorio Paolo Milani

    Nicolas Waespe and Heinz Hengartner are equally contributing senior authors

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    Cite this article

    Vogel, N., Schmugge, M., Renella, R. et al. The landscape of pediatric Diamond-Blackfan anemia in Switzerland: genotype and phenotype characteristics. Eur J Pediatr 180, 3581–3585 (2021). https://doi.org/10.1007/s00431-021-04146-4

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    • DOI: https://doi.org/10.1007/s00431-021-04146-4

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