Shorter birth length and decreased T-cell production and function predict severe infections in children with non-severe combined immunodeficiency cartilage-hair hypoplasia

Eetu Pello; Leena Kainulainen; Mikko Vakkilainen; Paula Klemetti; Mervi Taskinen; Outi Mäkitie; Svetlana Vakkilainen

doi:10.1016/j.jacig.2023.100190

Shorter birth length and decreased T-cell production and function predict severe infections in children with non-severe combined immunodeficiency cartilage-hair hypoplasia

J Allergy Clin Immunol Glob. 2023 Nov 22;3(1):100190. doi: 10.1016/j.jacig.2023.100190. eCollection 2024 Feb.

Authors

Eetu Pello^{1

2}, Leena Kainulainen³, Mikko Vakkilainen⁴, Paula Klemetti¹, Mervi Taskinen^{1

5}, Outi Mäkitie^{1

2

6

7}, Svetlana Vakkilainen^{1

2}

Affiliations

¹ Children and Adolescents, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
² Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
³ Department of Pediatrics and Adolescents, Turku University Hospital, University of Turku, Turku, Finland.
⁴ Department of Computer Science, Aalto University, Helsinki, Finland.
⁵ Department of Pediatric Hematology, Oncology and Stem Cell Transplantation (SCT), Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁶ Folkhälsan Institute of Genetics, Helsinki, Finland.
⁷ Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Background: Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the RMRP gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown.

Objective: We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients.

Methods: Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques.

Results: Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16⁺/56⁺ cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial "leaky" SCID-level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID-level lymphopenia.

Conclusions: Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.

Keywords: Immunodeficiency; RMRP; TREC; inborn error of immunity; lymphopenia; machine learning.