Twelve Iranian patients with a clinical and molecular diagnosis of DCLRE1C deficiency were identified, three of whom were excluded due to the unavailability of adequate clinical information. A total number of nine patients with DCLRE1C mutation (6 males and 3 females) from nine families were enrolled in this study. All patients, except P4 and P7, had consanguineous parents. All patients were born full-term with normal birth history. Family history of immunodeficiency disorders or early death was recorded in none of the patients’ documents, except for P3 whose older brother had died due to recurrent pneumonia at the age of 3 years old. A history of spontaneous abortion was observed in the family of 33.3% of patients. The median (IQR) age of onset was 6.0 (5–17.0) months. Severe combined immunodeficiency (SCID) was clinically detected at a median (IQR) age of 7.0 (6–20.5) months, following a median (IQR) diagnostic delay of 2.0 (1.0–3.5) months (Table 1).

The most common initial presentation was pneumonia (44.4%) and otitis media (33.3%), followed by Bacillus Calmette–Guérin (BCG) lymphadenitis (22.2%) and gastroenteritis (11.1%). The most prevalent manifestations during entire course of the disease were respiratory tract infections (including otitis media) (66.6%) and chronic diarrhea (66.6%). Three patients developed lymphoproliferation (two axillary lymphadenopathies following BCG vaccination, two splenomegaly, and one hepatomegaly). Two patients suffered from mucocutaneous lesions and failure to thrive (FTT). Moreover, autoimmunity was found in two patients, one patient had juvenile idiopathic arthritis (P5) and the other had celiac disease and idiopathic thrombocytopenic purpura (ITP) (P9). Two patients (P1 and P2) presented with allergic disorders in the form of food allergy and anaphylaxis. Malignancy was not found in any of the patients during median (IQR) 12 [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] months follow-up period.

In the immunologic evaluation, all patients were lymphopenic, except P1, P5 and P9 who had normal lymphocyte count. A lymphocyte subset study using flow cytometry revealed normal NK cell count, and reduced B cell and T CD4+ cell counts in all patients. In addition, T CD3+ and CD8+ cell counts were reduced in 7 patients (77.8%). Six patients (66.6%) were found to have low IgG serum levels. Low serum levels of IgA, IgM and IgE were detected in 77.8%, 55.5%, and 22.2% of individuals, respectively. Specific antibody response to diphtheria and tetanus was measured in 3 patients and was absent in all of them (Table 2). Genetic analysis was performed for 9 patients. Homozygous DCLRE1C mutation was found in all cases. Two patients from unrelated families had the same homozygous mutation in DCLRE1C (c.632G > T, p.G211V).Further details on mutation and related clinical features are discussed in the detailed information on the study population. All patients received Ig replacement therapy and prophylactic antibiotics. P1 was the only patient who underwent HSCT from his HLA-matched grandmother at the age of 11 months. Eventually, 11 days after transplantation died due to respiratory distress and pulmonary hemorrhage. For two patients, who are alive at the time of the current report, the severity and number of infections decreased. Unfortunately, other patients died due to disease-related complications.

P1 was the second child of consanguineous parents. His family history was unremarkable and his older brother was healthy. He was born full-term and had a normal birth history. Medical history included recurrent otitis media and skin rashes since 40 days of age with relapse after therapies with oral antibiotics. A history of food allergy was reported (the type of food was not mentioned) and the patient had an anaphylactic reaction in the form of dyspnea and flushing after a CT scan with contrast. At 2 months of age, he was admitted to the hospital with fever and otorrhea associated with cradle cap, diffuse skin rashes, and scaling skin rash. He received IV antibiotics (ceftriaxone 50 mg/kg) and corticosteroids (oral prednisolone and IV hydrocortisone). Further investigations confirmed generalized lymphadenopathy with some areas of central necrosis. Laboratory findings showed normal total lymphocyte count and normal NK cells, while reduced T CD3+, T CD4+, T CD8+ and B CD19+ cell count. Serum levels of immunoglobulins (IgG, IgM, IgA) were low. The lymphocyte transformation test (LTT) in response to BCG (1.2, normal ≥ 2.5) and phytohemagglutinin (PHA) stimulation was impaired (2.5, normal range ≥ 3). HIV real-time reverse transcription–polymerase chain reaction (RT-PCR) was negative. Genetic analysis revealed the deletion of exons 1 to 4 in the DCLRE1C gene. At 4 months of age Ig replacement therapy and prophylaxis with co-trimoxazole, acyclovir, fluconazole and isoniazid were started. He underwent HSCT from his HLA-matched grandmother at 11 months of age. However, 11 days after transplantation presented with pancytopenia and reduced systemic oxygen saturation, and finally died due to respiratory distress and pulmonary hemorrhage.

P2 was the only child of consanguineous parents. She was born full-term with normal birth and family history. Cow’s milk intolerance was reported. At 6 months of age, she presented with peripheral lymphadenopathy (left axillary and supraclavicular), abscess formation in the left axilla, and purulent discharge associated with swelling and erythema at the site of BCG vaccine injection. The blood culture was positive for Pseudomonas aeroginosa. Laboratory findings demonstrated low lymphocyte count and reduced all main lymphocyte subsets. Specific antibodies for tetanus and diphtheria were unprotective. The normal level of serum IgG associated with low IgA and IgM levels was detected. Nitroblue tetrazolium (NBT) was normal. Genetic analysis revealed a homozygous splicing mutation in the DCLRE1C gene (c.362 + 1G > T). She underwent axillary lymph node dissection, abscess drainage, and received Ig replacement therapy, anti-tuberclosis treatment with rifampin, ethambutol and isoniazid accompanied by IV vancomycin and meropenem. The specimen of left axillary abscess was positive for numerous acid fast bacili. She was discharged from the hospital with infection prophylaxis (metronidazole, cephalexin, itraconazole). After two weeks she was admitted to the hospital with multiple abscesses and lymphadenitis (axillary and supraclavicular), respiratory distress and pancytopenia. Eventually, she died due to septicemia at age 7 months.

P3 was the third child of consanguineous parents. She was born full-term with a normal birth history. Her older brother had died due to recurrent pneumonia when he was 3 years old, however, he was not assessed for immune deficiency.The second child was healthy. At 19 months of age, she presented to the hospital with mild diarrhea, low-grade fever, FTT, and cutaneous rashes around the mouth, genitalia, buttock, and both legs. Her medical history included recurrent skin rashes and mastoidectomy due to otitis media complications at 14 months of age. Further laboratory findings demonstrated low lymphocyte count and reduced all lymphocyte cell subsets but normal NK cell count. Moreover, the cytomegalovirus (CMV) PCR test in the whole blood sample was positive. Serum IgA was low, while serum IgG, IgM, and IgE were normal. The NBT test was normal and the LTT revealed a normal response to PHA (3.5, normal range ≥ 3), but it was impaired in response to BCG (1.7, normal range ≥ 2.5) and candida (1, normal range ≥ 2.5) stimulation. Genetic analysis revealed a homozygous missense mutation in DCLRE1C (c.632G > T, p.G211V). Monthly Ig replacement therapy and prophylaxis with co-trimoxazole, itraconazole and acyclovir were started. She is now 5 years old. She responded well to therapy, and a reduction in the rate and severity of infection was noted and now is in the waiting list for HSCT.

P4 was the only child of nonconsanguineous parents. She was born full-term with a normal birth history. At 6 months of age, she presented to the hospital with cough and diarrhea, unresponsive to outpatient treatment. Laboratory findings demonstrated low lymphocyte count, normal T CD3+ and T CD8+ accompanied by low T CD4+ and B CD19+ cell counts, and normal NK cell count. Serum IgG, IgM, and IgA were diminished. While the NBT test was normal. CMV DNA was detectable in the whole blood sample. Genetic analysis revealed the same homozygous mutation in the DCLRE1C gene (c.632G > T, p.G211V). At the age of 7 months, Ig replacement therapy was commenced. Finally, at the age of 4 years, she died due to severe pneumonia.

P5 was the second child of consanguineous parents. He was born full-term with normal birth history. The first child was spontaneously aborted. At the age of 10 years, he presented with fever, cough, and arthralgia. Medical history included oral candidiasis at two years, recurrent otitis media, skin rashes, juvenile idiopathic arthritis and severe osteoporosis. Laboratory findings demonstrated normal NBT test, normal total lymphocyte and expanded NK cell count, while decreased T and B cell counts. Low levels of IgG, IgM, and IgA were detected. Specific antibodies for tetanus and diphtheria were unprotective. Genetic analysis revealed homozygous frameshift DCLRE1C mutation (c.1250_1260delCAATGACCTGCA, p.S417YfsX459) and Ig replacement therapy was commenced. Unfortunately, he died due to encephalitis at 13 years of age.

P6 was the second child of consanguineous parents. He was born full-term with normal birth history. No information about the health status of the first child has been reported. At 8 months of age, he was admitted to the hospital with cough, diarrhea, and respiratory distress. His medical history included recurrent respiratory infections. Laboratory findings demonstrated low lymphocyte count, reduced T CD3+, T CD4+, T CD8+ and B CD19+ cells count, but normal NK cells count. Serum IgG level was low, whereas serum IgM and IgA were within normal range. Genetic analysis revealed a homozygous stopgain mutation in the DCLRE1C gene (c.1162G > A, p.E388X). Although he received infection prophylaxis with co-trimoxazole, itraconazole and acyclovir, Finally, he died of severe pneumonia at the age of 12 months.

P7 was the only child of nonconsanguineous parents. He was full term with normal birth history. Medical history and family history were unremarkable. At 5 months of age, he presented to the hospital with fever, cough, diarrhea, generalized lymphadenopathy, and hepatosplenomegaly. Laboratory findings demonstrated low lymphocyte count, reduced T CD3+, T CD4+, T CD8+, B CD19+ cell counts, and normal NK cell count. Serum immunoglobin production including IgG, IgA, and IgM were all normal. Genetic analysis revealed a homozygous missense mutation in the DCLRE1C gene (c.329 T > G, p.L110R). Finally, at the age of 7 months, he died due to sepsis.

P8 was the third child of consanguineous parents. He was born full-term with normal birth history and family history. Other sibilings were healthy. At the age of 5 months he was admitted to the hospital with several complaints including fever, oral candidiasis, erythema and swelling at the site of the BCG vaccination, disseminated lymphadenopathy, and hepatomegaly. The BCGosis was confirmed and he underwent anti-tuberculosis treatment with rifampin, isoniazid, and ethambutol, Further laboratory findings demonstrated low lymphocyte count, reduced all lymphocyte subsets including CD3, CD4 and CD8 T cell and CD19 B cell, despite normal NK cells count. Serum immunoglobulin (IgG, IgM, IgA) levels were low. Genetic analysis revealed a homozygous large deletion (Exon 1-3) in the DCLRE1C gene. Immunoglobin replacement and prophylaxis with co-trimoxazole, acyclovir and fluconazole were commenced. Unfortunately, at the age of 10 months, he died due to cardiopulmonary arrest.

P9 was the second child of consanguineous parents. He was born full-term with normal birth history. The first child was spontaneously aborted. At 19 months of age, he presented with FTT and diarrhea. His medical history included recurrent respiratory infection and celiac disease since he was 5 months. Additionally, at 2 years old, diagnosis of ITP was confirmed. Further laboratory findings demonstrated normal lymphocyte count, normal T CD3+, T CD8+, NK cells count, and reduced T CD4+ and B CD19+ cells count. Serum IgG and IgA levels were low but IgM was normal. Genetic analysis revealed a homozygous missense mutation in the DCLRE1C gene (c.41G > T, p.G14V). He is now 24 years old. He underwent Ig replacement therapy. He responded well and a reduction in the rate and severity of infections was noted.