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TREC Screening for WHIM Syndrome

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

A Publisher Correction to this article was published on 28 January 2021

This article has been updated

Abstract

Purpose

T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined immunodeficiencies (SCID). However, other primary immunodeficiency diseases (PID) have also been identified as the result of TREC screening. We recently reported a newborn with a low TREC level on day 1 of life who was diagnosed with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome, a non-SCID primary immunodeficiency caused by mutations in the chemokine receptor CXCR4.

Methods

We have now retrospectively reviewed the birth and clinical histories of all known WHIM infants born after the implementation of NBS for SCID.

Results

We identified six infants with confirmed WHIM syndrome who also had TREC quantification on NBS. Three of the six WHIM infants had low TREC levels on NBS. All six patients were lymphopenic but only one infant had a T cell count below 1,500 cells/μL. The most common clinical manifestation was viral bronchiolitis requiring hospitalization. One infant died of complications related to Tetralogy of Fallot, a known WHIM phenotype.

Conclusion

The results suggest that WHIM syndrome should be considered in the differential diagnosis of newborns with low NBS TREC levels.

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Data Availability

All data collected is submitted in Tables 1, 2, and 3.

Change history

Abbreviations

ALC:

Absolute lymphocyte count

ANC:

Absolute neutrophil count

CD:

Cluster of differentiation

Ct:

Cycle threshold number

CXCR4:

C-X-C chemokine receptor type 4

DOL:

Day of life

G-CSF:

Granulocyte colony-stimulating factor

IgRT:

Immunoglobulin replacement therapy

m:

Month

mcg:

Microgram

ml:

Milliliter

NBS:

Newborn screen

NICU:

Neonatal intensive care unit

PID:

Primary immunodeficiency

RTEs:

Recent thymic emigrants

SCID:

Severe combined immunodeficiency

TRECs:

T cell receptor excision circles

WBC:

White blood count

WGS:

Whole-genome sequencing

WHIM:

Warts, hypogammaglobulinemia, infections, myelokathexis

y:

Year

References

  1. Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71 Published 2012 Sep 25.

    Article  Google Scholar 

  2. Aghamohammadi A, Abolhassani H, Puchalka J, Greif-Kohistani N, Zoghi S, Klein C, et al. Preference of genetic diagnosis of CXCR4 mutation compared with clinical diagnosis of WHIM syndrome. J Clin Immunol. 2017;37(3):282–6.

    Article  CAS  Google Scholar 

  3. Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM syndrome: from pathogenesis towards personalized medicine and cure. J Clin Immunol. 2019;39(6):532–56. https://doi.org/10.1007/s10875-019-00665-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Evans MO 2nd, McDermott DH, Murphy PM, Petersen MM. Abnormal newborn screen in a WHIM syndrome infant. J Clin Immunol. 2019;39(8):839–41. https://doi.org/10.1007/s10875-019-00686-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mentzer WC, Johnston RB, Baehner RL, Nathan DG. An unusual form of chronic neutropenia in a father and daughter with hypogammaglobulinaemia. Br J Haematol. 1977;36:313–22.

    Article  Google Scholar 

  6. Amatuni G, Currier R, Church J, Bishop T, Grimbacher E, Nguyen A, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California, 2010-2017. Pediatrics. 2019;143:2.

    Article  Google Scholar 

  7. Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States [published correction appears in JAMA. 2014 Nov 26;312(20):2169. Bonagura, Vincent R [added]]. JAMA. 2014;312(7):729–38.

    Article  Google Scholar 

  8. Gans MD, Gavrilova T. Retrospective analysis of a New York newborn screen severe combined immunodeficiency referral center. J Clin Immunol. 2020;40(3):456–65.

    Article  CAS  Google Scholar 

  9. Dotta L, Notarangelo L, Moratto D, Kumar R, Porta F, Soresina A, et al. Long-term outcome of WHIM syndrome in 18 patients: high risk of lung disease and HPV-related malignancies. J Allergy Clin Immunol Pract. 2019;7(5):1568–77.

    Article  Google Scholar 

  10. Balabanian K, Brotin E, Biajoux V, Bouchet-Delbos L, Lainey E, Fenneteau O, et al. Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice. Blood. 2012;119(24):5722–30. https://doi.org/10.1182/blood-2012-01-403378.

    Article  CAS  PubMed  Google Scholar 

  11. Gul KA, Strand J, Pettersen RD, Brun H, Abrahamsen TG. T-cell receptor excision circles in newborns with heart defects. Pediatr Cardiol. 2020;41(4):809–15. https://doi.org/10.1007/s00246-020-02317-y.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gul KA, Øverland T, Osnes L, Baumbusch LO, Pettersen RD, Lima K, et al. Neonatal levels of T-cell receptor excision circles (TREC) in patients with 22q11.2 deletion syndrome and later disease features. J Clin Immunol. 2015;35(4):408–15. https://doi.org/10.1007/s10875-015-0153-5.

    Article  CAS  PubMed  Google Scholar 

  13. van der Spek J, Groenwold RH, van der Burg M, van Montfrans JM. TREC based newborn screening for severe combined immunodeficiency disease: a systematic review. J Clin Immunol. 2015;35(4):416–30.

    Article  Google Scholar 

  14. Patrawala M, Kobrynski L. Nonsevere combined immunodeficiency T-cell lymphopenia identified through newborn screening. Curr Opin Allergy Clin Immunol. 2019;19(6):586–93. https://doi.org/10.1097/ACI.0000000000000586.

    Article  CAS  PubMed  Google Scholar 

  15. Barry JC, Crowley TB, Jyonouchi S, Heimall J, Zackai EH, Sullivan KE, et al. Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. J Clin Immunol. 2017;37(5):476–85. https://doi.org/10.1007/s10875-017-0403-9.

    Article  CAS  PubMed  Google Scholar 

  16. Albin-Leeds S, Ochoa J, Mehta H, Vogel BH, Caggana M, Bonagura V, et al. Idiopathic T cell lymphopenia identified in New York state newborn screening. Clin Immunol. 2017;183:36–40. https://doi.org/10.1016/j.clim.2017.07.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Trampont PC, Tosello-Trampont AC, Shen Y, Duley AK, Sutherland AE, Bender TP, et al. CXCR4 acts as a costimulator during thymic beta-selection. Nat Immunol. 2010;11(2):162–70. https://doi.org/10.1038/ni.1830.

    Article  CAS  PubMed  Google Scholar 

  18. Chatterjee S, Behnam Azad B, Nimmagadda S. The intricate role of CXCR4 in cancer. Adv Cancer Res. 2014;124:31–82. https://doi.org/10.1016/B978-0-12-411638-2.00002-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Poulain S, Roumier C, Venet-Caillault A, Figeac M, Herbaux C, Marot G, et al. Genomic landscape of CXCR4 mutations in Waldenström Macroglobulinemia. Clin Cancer Res. 2016;22(6):1480–8. https://doi.org/10.1158/1078-0432.CCR-15-0646.

    Article  CAS  PubMed  Google Scholar 

  20. Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. 2009;16(1):20–6.

    Article  CAS  Google Scholar 

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Funding

This work was supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA (Grant# AI000615–28), National Institute of Allergy and Infectious Diseases, National Institutes of Health-funded CXCR4 gene sequencing and clinical encounters for multiple patients.

Author information

Authors and Affiliations

  1. Blanchfield Army Community Hospital, Fort Campbell, KY, USA

    Martin Oman Evans II

  2. Walter Reed National Military Medical Center, Bethesda, MD, USA

    Maureen M. Petersen

  3. Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Amer Khojah

  4. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Soma C. Jyonouchi

  5. Wright-Patterson Medical Center, Wright-Patterson Air Force Base, Wright-Patterson AFB, OH, USA

    George S. Edwardson

  6. Vanderbilt University Medical Center, Nashville, TN, USA

    Yasmin West Khan & James Albert Connelly

  7. Dayton Children’s Hospital, Dayton, OH, USA

    David Morris

  8. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Shamik Majumdar, David H. McDermott & Philip M. Murphy

  9. University of South Florida and Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA

    Jolan E. Walter

  10. Massachusetts General Hospital for Children, Boston, MA, USA

    Jolan E. Walter

Authors
  1. Martin Oman Evans II
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  4. Soma C. Jyonouchi
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  9. Shamik Majumdar
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Contributions

M.E., M.P., D.M., A.K., S.J., Y.K., J.C., and D.M. provided medical care for the patients. M.E., M.P., D.M., A.K., S.J., Y.K., J.C., D.M., P.M., G.E., and J.W. assisted with data gathering. M.E., G.E., J.C., A.K., and S.J. spoke with state newborn screening labs. S.M. performed mice studies as well as manuscript editing. M.E., M.P., P.M., and D.M. wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Martin Oman Evans II.

Ethics declarations

Three patients were enrolled in the National Institutes of Health (NIH) study 14-I-0185. Informed consent was obtained and all data appropriately de-identified. Three other patients were enrolled in an IRB-approved protocol at the University of South Florida and Johns Hopkins All Children’s Hospital (USF) that allowed collection of data on patients with WHIM syndrome from collaborating sites. NIH and USF contributed this de-identified data for joint analysis and publication.

Conflict of Interest

J.E.W. has received grants as principal investigator on investigator-initiated translational studies and sponsored clinical trials of patients with WHIM syndrome funded by X4 Pharmaceuticals.

Unrelated:

J.E.W. has been an advisory board member, speaker bureau participant and site-principal investigator for a trial funded by Takeda (former Shire) outside of the submitted work.

J.E.W. has also run sponsored studies for Lediant, Octapharma, and Momenta as site principal investigator outside of the submitted work.

Consent to Participate

Freely-given, informed consent to participate in the study was obtained from parent or legal guardians for each infant.

Consent for Publication

Consent from individuals to publish de-identified data was included in NIH and USF enrollment consents.

Disclaimer

The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Army, DOD, or the U.S. Government.

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The original online version of this article was revised: It contained errors in Tables 1 and 3.

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Evans, M.O., Petersen, M.M., Khojah, A. et al. TREC Screening for WHIM Syndrome. J Clin Immunol 41, 621–628 (2021). https://doi.org/10.1007/s10875-020-00921-4

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  • DOI: https://doi.org/10.1007/s10875-020-00921-4

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