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.
Objective: To provide clinical and immunological insights obtained from two unrelated patients who displayed clinical characteristics of CHH.
Methods: Two patients with suspected CHH syndrome due to skeletal dysplasia and immunodeficiency, underwent immunological and genetic work-up using flow cytometry, immune repertoire next-generation sequencing (NGS), and Sanger sequencing to identify the underlying defects.
Results: P1 presented with low birth weight and skeletal dysplasia. Newborn screening (NBS) was suggestive of T cell immunodeficiency as T cell receptor excision circle (TREC) levels were undetectable. Both T cell receptor (TCR) - Vβ and T-cell receptor gamma (TRG) repertoire were restricted with evidence of clonal expansion. Genetic analysis identified compound heterozygous variants inherited from both parents in RMRP. P2 presented with recurrent lung and gastrointestinal infections, skeletal dysplasia, failure to thrive and hepatomegaly. TCRβ repertoire revealed a normal polyclonal pattern with only slight overexpression of TCR-βV20 and several restricted expression of Vβs. TRG expressed a normal diverse repertoire, similar to the healthy control sample. Genetic analysis identified bi-allelic novel regulatory variants in RMRP. Both parents are carriers of this mutation.
Conclusion: Our findings demonstrate how immunological work-up, supported by genetic findings can dramatically change the suggestive 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