A 19 month old male presented to the office for evaluation of recurrent ear infections. His mother reported three to four infections which required antibiotics. He had required extended courses of antibiotics, but not IV antibiotics. There was no history of pneumonia, skin abscesses, suppurative adenitis, osteomyelitis, sepsis (bacterial or fungal), or cellulitis/impetigo. He was otherwise healthy with a history of mild atopic dermatitis.
On exam, his vitals were within normal limits for age. His physical exam was unremarkable except for dry, erythematous patches behind the knees, bilateral antecubital fossa, and axilla.
At the time of initial presentation the patient was living with his biological mother, and two half-brothers. Two older half-brothers were removed from his mother's care prior. He did not attend day care. Mother denied consanguinity with his biological father; in addition, all of her five children had different fathers. There were no pets in the home.
Family history was significant for serious infections in other family members. The patient's maternal grandfather died at an early age (around age 30 years) due to pneumonia. A half-brother in foster care with a history of severe infections was diagnosed with CGD based on DHR. Genetic testing revealed a novel c141+4 A>G mutation of the CYBB gene that is not a common benign variant in individuals with European or African American ancestry. Two of three in-silico splice prediction models (NetGene2, Softberry) predicted damage to the splice donor site for intron 2. A third model (BDGP) predicted no effect on splicing. In the absence of RNA/functional studies, the actual effect of the sequence change is unknown so the mutation was classified as a variant of uncertain significance. A second half-brother in foster care with a different family had been admitted at this academic institution with Burkholderia sepsis and died. While this same child had infection with salmonella at 2 years of age, the diagnosis of CGD was not known at the time of admission. Due to the severity and quick onset of his illness, CGD testing was not obtained. CGD testing could not be completed post-mortem. The diagnosis of CGD was suspected because of his infection with Burkholderia spp. The mother was located and testing confirmed that she was an X-linked carrier of CGD. Based on this result our patient and his two half-brothers were seen for evaluation and testing in our clinic. Subsequently, his mother learned about the CGD diagnosis of her sister's son (Figure 1).
The DHR was grossly abnormal (Figure 2A, control; Figure 2B, patient) consistent with the diagnosis of CGD. One of the two half-brothers also tested positive for CGD, the other tested negative. The patient was started on trimethoprim-sulfamethoxazole and itraconazole prophylaxis and also referred to Hematology/Oncology for HSCT evaluation.
After careful consideration of the risks and benefits, Hematology/Oncology recommended proceeding with HSCT as the only chance of curing the patient's underlying CGD. As previously discussed, RIC regimens are favored over MAC regimens due to the lower risk of transplant-related toxicities and mortality. The use of donor bone marrow or peripheral blood stem cells (PBSCs) as the stem cell source with a RIC regimen is favored over umbilical cord stem cells due to the high risk of graft failure with cord blood transplantation after RIC. Bone marrow sources are preferred over PBSCs due to the lower incidence of chronic graft-vs.-host disease.
As the patient did not have any known full siblings, the next best stem cell source is bone marrow from a highly HLA-matched unrelated donor. The search for a healthy, full-HLA match is ongoing with plans to proceed with HSCT when an appropriate donor is identified.