Results:
The index patient III.1 (previously published11) is 24-year-old male, who was diagnosed with EBV positive classical Hodgkin lymphoma (cHL) of nodular sclerosis histology at 11 year of age. He achieved complete remission with multiagent chemotherapy and radiation. Subsequently, he developed autoimmune hemolytic anemia (AIHA), and then immune thrombocytopenia (ITP). At 17 years of age, he was diagnosed with autoimmune lymphoproliferative syndrome (ALPS), and further genetic testing revealed heterozygous CTLA-4 splice mutation c.458-1G>C. Four years later, the patient developed autoimmune lymphocytic enterocolitis (ALE). A year later, at 22 years of age, he was diagnosed with a new EBV+ cHL of mixed cellularity subtype. He was treated with further courses of chemotherapy, and complete remission was achieved. Further, the patient underwent allogeneic peripheral stem cell transplantation from matched unrelated donor. At the present time, he remains in complete remission from both cHL, and autoimmune conditions.
Patient III.3 is 14 years old male, and is the maternal cousin brother of the proband. He developed chronic progressive diarrhea since he was 1 year old. At the age of 5 years, he developed multiple recurrent anal warts. Esophagogastroduodenoscopy (EGD) and colonoscopy revealed ALE. He was started on oral tacrolimus, which improved his symptoms. He was treated with multiple courses of corticosteroids. Few months later, he developed right upper quadrant abdominal pain. Imaging studies demonstrated multiple small gallbladder calculi and choledocholithiasis, requiring ERCP and removal of CBD stones. A trial of sirolimus worsened his symptoms and he had to be restarted back on tacrolimus with improvement in his gastrointestinal symptoms. His genetic testing revealed the same CTLA-4 spice site mutation as the proband. Since the age of 12 years, he was started on abatacept, a fusion protein composed of Fc region of the IgG1 fused to the extracellular domain of CTLA-4, every 4 weeks, along with low dose tacrolimus and sirolimus with good improvement of symptoms. He has developed multiple nutritional deficiencies such as copper, vitamin A, and vitamin D, which improved with supplementation. Of note, patient also developed chronic EBV viremia since the age of 10 years. However, no signs of lymphoma or lymphoproliferative disorders have been identified.
Patient III.4 is the paternal cousin sister of the proband, who is 20 years old. She developed ITP at 9 years of age. When she was 12 years old, she was admitted with chronic diarrhea and excessive weight loss, prompting EGD and colonoscopy, which revealed ALE. The genetic testing confirmed CTLA4 c.458-1 G>C mutation. She was started on oral tacrolimus since the age of 14 years, with near complete resolution of GI symptoms associated with ALE. Of note, she was also found to have EBV viremia since the age of 16 years. However, she has not developed lymphoproliferative disorders or lymphoma.
Patient II.3 is the maternal uncle of the proband, and the father of patient III.3 and III.4. He is 43 years old and was diagnosed with ALE at 28 years of age. Later, he was found to have chronic hypogammaglobinemia and was clinically diagnosed with common variable immunodeficiency (CVID). He developed AIHA at the age of 29 years. When he was 32 years old, he was diagnosed with atypical marginal zone non-Hodgkin lymphoma with CNS metastasis. No genetic testing has been performed.
Patient II.5 is the maternal uncle of the proband, who had history of cataract at the age of 6 years. He also had history of multiple surgeries for glaucoma in his childhood. He was diagnosed with juvenile rheumatoid arthritis at the age of 9 months. Later, he developed ITP, AIHA, ALE, hypothyroidism, hypogonadism and insulin dependent DM.