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Immunologic Heterogeneity in 2 Cartilage-Hair Hypoplasia Patients With a Distinct Clinical Course

Gamliel A1,2, Lee YN1,2, Lev A1,2, AbuZaitun O3, Rechavi E1,2, Levy S1, Simon AJ1,4*, Somech R1,2*

Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
3Ambulatory Pediatrics, Nablus, Palestinian Authority
4Hematology Laboratory, Hemato-Immunology Unit, and Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel
*Both authors jointly supervised this work

J Investig Allergol Clin Immunol 2023; Vol 33(4) : 263-270
doi: 10.18176/jiaci.0792

Introduction: Cartilage-hair hypoplasia (CHH) syndrome is a rare autosomal recessive syndrome associated with skeletal dysplasia, varying degrees of combined immunodeficiency (CID), short stature, hair hypoplasia, macrocytic anemia, increased risk of malignancies, and Hirschsprung disease.
Purpose: To provide clinical and immunological insights obtained from 2 unrelated patients who displayed clinical characteristics of CHH.
Methods: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency underwent an immunological and genetic work-up using flow cytometry, next-generation sequencing (NGS) of the immune repertoire, and Sanger sequencing to identify the underlying defects.
Results: Patient 1 presented with low birth weight and skeletal dysplasia. Newborn screening was suggestive of T-cell immunodeficiency, as T-cell receptor excision circle levels were undetectable. Both the T-cell receptor (TCR) Vß and TCR-g (TRG) repertoires were restricted, with evidence of clonal expansion. Genetic analysis identified compound heterozygous RMRP variants inherited from both parents. Patient 2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive, and hepatomegaly. The polyclonal pattern of the TCRß repertoire was normal, with only slight overexpression of TCR-ßV20 and restricted expression of Vßs. TRG expressed a normal diverse repertoire, similar to that of the healthy control sample. Genetic analysis identified biallelic novel regulatory variants in RMRP. Both parents are carriers of this mutation.
Conclusion: Our findings demonstrate how the immunological work-up, supported by genetic findings, can dramatically change treatment and future outcome in patients with the same clinical syndrome.

Key words: RMRP, Severe combined immunodeficiency (SCID), Cartilage-Hair Hypoplasia (CHH), NGS, TCR repertoire

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