To the editor: Cytidine 5’triphosphate (CTP) is an important precursor for DNA, RNA, phospholipid synthesis, and protein sialylation, needed for cell proliferation and function. CTP is produced either via de novo synthesis or a salvage pathway, both of which depend on CTP synthases (CTPS). The mammalian CTPS isozymes, CTPS1 and CTPS2, share 74% amino acid identity [1]. Although their respective roles are not fully understood, CTPS have a unique ability to bind to four nucleotides (ATP, UTP, GTP, and CTP) and sense intracellular concentrations of these nucleotides and glutamine. Control of CTP synthesis appears to be strictly regulated, as suggested by the fact that the cellular concentration of CTP is the lowest [2]. Human lymphocytes dramatically increase CTP levels following mitogenic stimulation, indicating that CTP synthase activity is an important step for DNA synthesis in lymphocytes [3]. This important role of CTPS was recently highlighted, showing homozygous loss-of-function mutations in CTPS1 in patients of British ancestry [4]. The original study included eight patients from six unrelated families from Northern England, with a shared clinical phenotype of combined immune deficiency (CID) characterized by recurrent infections, due to Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV), and encapsulated bacterial infections. The authors reported defective T cell proliferation in response to activation by antigens, anti-CD3 or anti-CD3/CD28, with weak or no impact on TCR-mediated cytokine production, and CD8 degranulation, respectively. Six of eight patients were reported to have undergone hematopoietic stem cell transplantation (SCT); however, their transplant and posttransplant courses were not discussed. No similar cases have been published since the original description. Here, we report two sisters with homozygous CTPS1 mutations, identified by exome sequencing. Similar to the previously published cases [4], these siblings, born to a nonconsanguineous family, whose ancestors emigrated from Northern England, suffered from recurrent sino-pulmonary and viral infections, due to VZV and EBV. Both have undergone SCT for chronic active EBV infection and CID and currently are in excellent health, 10 and 11 years post-transplant. Both patients’ immunological and SCT data are summarized in Table 1.

The index patient, patient 1 (Pt1) presented at the age of 3 with a history of recurrent sino-pulmonary infections and recalcitrant varicella. At the age of 18 months, she developed vesicular lesions on her legs, following administration of the varicella vaccine. One month later, she developed generalized varicella, with VZV isolated from a typical lesion and from blood. Although this acute episode improved with acyclovir, as the months ensued, she suffered from recalcitrant vesicular eruptions, including one episode with corneal involvement and presumed varicella hepatitis. At 2 years of age, Pt1 developed left-sided paralysis with CT/MRI/MRA findings consistent with a stroke, from which she recovered completely. At that time, EBV serology demonstrated primary acute infection. No spinal fluid or blood viral PCR studies were performed. At 3 years of age, due to recurrent pneumonia, bronchoscopy was performed, which yielded Bordetella bronchiseptica. There was no evidence of bronchiectasis on high-resolution chest CT (HRCT). Laboratory assessment, prior to referral,