The dilemma of X-linked agammaglobulinemia carriers

Federica Pulvirenti¹, Cinzia Milito², Francesco Cinetto³, Giulia Garzi², Germano Sardella⁴, Giuseppe Spadaro⁵, Francesca Lippi⁶, Valentina Guarnieri⁶, Bianca Laura Cinicola^{2

7}, Maria Carrabba⁸, Daniele Guadagnolo², Giovanna Fabio⁸, Baldassarre Martire⁹, Caterina Cancrini^{10

11}, Giulia Lanzoni¹², Andrea Finocchi^{10

11}, Gigliola Di Matteo^{10

11}, Eva Pompilii¹³, Simona Ferrari¹³, Isabella Quinti²

Affiliations

¹ Reference Centre for Primary Immune Deficiencies, Sapienza University Hospital Policlinico Umberto I, Rome, Italy.
² Department of Molecular Medicine, Sapienza University, Rome, Italy.
³ Rare Diseases Referral Center, Internal Medicine 1, Ca' Foncello Hospital, Treviso, Department of Medicine-DIMED, University of Padova, Padua, Italy.
⁴ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
⁶ Immunology Division, Section of Pediatrics, Meyer Children's Hospital IRCCS, Florence, Italy.
⁷ Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.
⁸ Department of Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁹ Pediatrics and Neonatology Unit, Maternal-Infant Department, Monsignor A. R. Dimiccoli Hospital, Barletta, Italy.
¹⁰ Research Unit of Primary Immunodeficiencies, Academic Department of Pediatrics, UOC Clinical Immunology and Vaccinology IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
¹¹ Department of Systems Medicine University of Rome Tor Vergata, Rome, Italy.
¹² Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹³ Next Fertility GynePro, NextClinics International, Bologna, Italy.

PMID: 39867744
PMCID: PMC11759626
DOI: 10.1016/j.jacig.2024.100384

The dilemma of X-linked agammaglobulinemia carriers

Federica Pulvirenti et al. J Allergy Clin Immunol Glob. 2024.

. 2024 Dec 12;4(1):100384.

doi: 10.1016/j.jacig.2024.100384. eCollection 2025 Feb.

Authors

Affiliations

¹ Reference Centre for Primary Immune Deficiencies, Sapienza University Hospital Policlinico Umberto I, Rome, Italy.
² Department of Molecular Medicine, Sapienza University, Rome, Italy.
³ Rare Diseases Referral Center, Internal Medicine 1, Ca' Foncello Hospital, Treviso, Department of Medicine-DIMED, University of Padova, Padua, Italy.
⁴ Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
⁶ Immunology Division, Section of Pediatrics, Meyer Children's Hospital IRCCS, Florence, Italy.
⁷ Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy.
⁸ Department of Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁹ Pediatrics and Neonatology Unit, Maternal-Infant Department, Monsignor A. R. Dimiccoli Hospital, Barletta, Italy.
¹⁰ Research Unit of Primary Immunodeficiencies, Academic Department of Pediatrics, UOC Clinical Immunology and Vaccinology IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
¹¹ Department of Systems Medicine University of Rome Tor Vergata, Rome, Italy.
¹² Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹³ Next Fertility GynePro, NextClinics International, Bologna, Italy.

PMID: 39867744
PMCID: PMC11759626
DOI: 10.1016/j.jacig.2024.100384

Abstract

Background: Many patients with X-linked agammaglobulinemia (XLA) nowadays have reached adulthood, as well as their sisters, possibly carriers of a deleterious Bruton tyrosine kinase variant. Studies on motherhood outcomes in families with XLA are lacking.

Objective: We sought to investigate adherence to carrier status screening, interest in preconception and prenatal genetic counseling, and reproductive decisions in relatives with XLA.

Methods: In this multicenter, retrospective cohort study, we collected a 3-generation pedigree and data on mothers and sisters of patients with XLA, including carrier status and pregnancy outcome.

Results: Data on 53 adults with XLA, 52 mothers, and 33 sisters were collected. All XLA sisters received genetic counseling. Forty percent of the sisters chose to undergo carrier status determination, and 60% of them chose invasive prenatal testing. The main reasons for the sisters to decide not to undergo genetic testing were their young age and the willingness to carry on with the pregnancy regardless of the outcome of the genetic test, followed by the willingness to postpone the decision at the time of pregnancy and the decision to not have children. Prenatal testing resulted in 5 XLA diagnoses, with 2 pregnancy terminations, 1 miscarriage, and 2 XLA live births. Three carriers refused prenatal testing and had 6 live births, including 3 XLA-affected sons. One sister was diagnosed as a carrier after the birth of an XLA-affected son. In total, 9 XLA diagnoses were made, including 6 live births.

Conclusions: A number of XLA sister carriers decided to carry on with their pregnancy after receiving the diagnosis of an affected fetus or after refusing prenatal testing. We propose to initiate a more extensive collaborative study to verify the effect of genetic counseling on families with XLA in other cohorts from different countries.

Keywords: Bruton; X-linked agammaglobulinemia; XLA; carrier; genetic counseling; genetic diagnosis; inborn errors of immunity; pregnancies; prenatal testing.

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Conflict of interest statement

This study received funding from the European Union—NextGenerationEU through the Italian Ministry of University and Research (under PNRR-M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to I.Q.; CUP: B53C22004000006). The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Figures

**Fig 1**
Reproductive outcomes of the family members of patients with XLA, who are represented by *red* shapes. Female patients carrying a pathogenic *BTK* variant (carriers) are represented by *red*/*gray* shapes; female and male patients carrying wild-type (WT) *BTK* variants are represented by *pink* and *blue* shapes, respectively.

See this image and copyright information in PMC

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The dilemma of X-linked agammaglobulinemia carriers

Affiliations

The dilemma of X-linked agammaglobulinemia carriers

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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