Reference no: EM133647808

Assignment:

Mr and Mrs Causubon had a normal daughter 3 years after they were married. Two years later they had a son and named him Martin. He weighed 3.5 kg at birth and seemed to be perfectly normal. At 3 months of age, Martin developed a runny nose and a persistent dry cough. One month later he had a middle ear infection (otitis media) and his pediatrician treated him with amoxicillin. At 5 months of age Martin had a recurrence of otitis media. His cough persisted and a radiological examination of his chest revealed the presence of pneumonia in both lungs. He was treated with another antibiotic, clarithromycin. Mrs Causubon noticed that Martin had thrush (Candida spp.) in his mouth and an angry red rash in the diaper area. He was not gaining weight; he had been in the 50th percentile for weight at age 2 months, but by 6 months he had fallen to the 3rd percentile. His pediatrician had given him diphtheria-pertussis-tetanus (DPT), hemophilus, pneumococcus, and inactivated polio vaccine at 2, 4, and 6 months, according to the calendar.

Martin's pediatrician referred him to the Children's Hospital for further studies. On admission to the hospital, he was fretful and had tachypnea (fast breathing). A red rash was noted in the diaper area as well as white flecks of thrush on his tongue and buccal mucosa. His tonsils were very small. He had a clear discharge from his nose, and cultures of his nasal fluid grew Pseudomonas aeruginosa. Coarse, harsh breath sounds were heard in both lungs. His liver was slightly enlarged.

Martin's white blood count was 4800 cells/μl (normal 5000-10,000 cells/μl) and his absolute lymphocyte count was 760 cells/μl (normal 3000 lymphocytes/μl). None of his lymphocytes were stained by an antibody to CD3, and it was concluded that he had no T cells. Ninety-nine percent of his lymphocytes bound antibody against the B-cell molecule CD20, and 1% were natural killer (NK) cells reacting with anti-CD16. His serum contained IgG at a concentration of 30 mg/dl, and IgM at 12 mg/dl. Serum IgA were undetectable. His blood mononuclear cells were completely unresponsive to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen, as well as to specific antigens to which he had been previously exposed by immunization or infection-tetanus and diphtheria toxoids, and to Candida antigen. His red cells contained normal amounts of adenosine deaminase and purine nucleoside phosphorylase. Cultures of sputum for bacteria and viruses revealed the abundant presence of respiratory syncytial virus (RSV).

At this point a blood sample was obtained from Martin's mother to examine her T cells for random inactivation of the X chromosome. It was found that her T cells exhibited complete nonrandom X-chromosome inactivation. Search for mutations in the IL2RG gene revealed deletion of a single A nucleotide in exon 2, leading to a frameshift. HLA typing showed that Martin's sister had no matching HLA alleles. His parents, as expected, each shared one HLA haplotype with Martin.

Martin was treated with intravenous gamma globulin at a dose of 0.5 g/kg body weight every 3 weeks, and his serum IgG level was maintained at 600 mg/dl by subsequent IgG infusions. He was given aerosolized ribavirin to control his RSV infection and trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis jirovecii. Without any chemotherapy, Martin was given 5e6 /kg CD34+ cells that had been purified from his mother's bone marrow. Three months after receiving the maternal bone marrow, Martin's blood contained 600 maternal CD3+ T cells/μl, which responded to PHA. His immune system was slowly reconstituted over the ensuing 3 months, but he remained unable to produce IgA and to make specific IgG antibodies. Therefore, Martin continues to require substitution therapy with intravenous immunoglobulin (400 mg/kg every 3 weeks).

• What is IL2RG and why does it's mutation result in only T cell deficiency?
• Why was Martin given CD34+ cells as a treatment?
• This treatment restored his CD3+ T cell count. If these T cells are responsive to PHA, why would this treatment NOT have fixed his lack of IgA and IgG antibody production?
• Patients with immunodeficiency diseases should never be given live viral vaccines! Why not?