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.