Wiedemann-Steiner syndrome (WSS) is characterized by developmental delays, short stature, characteristic facial features, multisystem congenital anomalies, and hypertrichosis (especially hypertrichosis cubiti, or hairy elbows) [1]. Approximately 250 cases have been reported, and at least 89 likely pathogenic monoallelic variants identified in its causative gene, KMT2A. Though autosomal dominant, over 55% of KMT2A mutations are de novo [1-3]. Recent identification of novel KMT2A variants has illuminated significant heterogeneity in genotype–phenotype correlation with WSS and its increasing association with immunodeficiency [1-7].
We present a 10-year-old male with developmental delays, congenital cardiac defects, horseshoe kidney with VUR and recurrent UTIs, pyloric stenosis, constipation, and poor dentition, diagnosed with Hodgkin lymphoma at age 8. He achieved remission after six cycles of therapy but relapsed within 18 months. During treatment, he was hospitalized multiple times for pneumonia. BAL on separate occasions revealed EBV and Haemophilus influenzae. Before lymphoma, he had recurrent skin and respiratory infections. Immunologic evaluation with lymphocyte subsets at initial diagnosis showed lymphopenia with proportionally decreased T and B cell subsets. IgG and IgM were low-normal with elevated IgA. Four months off therapy, CD4 lymphopenia persisted with normal CD8 and B cell numbers with an inverted CD4/CD8 ratio. Evaluation is limited given the influence of immunochemotherapy. Respiratory infections persisted despite scheduled IVIG. Whole exome found a likely pathogenic, de novo nonsense mutation in KMT2A (c.9487 C>T p.(Arg3283Ter).
This fits the WSS phenotype, including hypertrichosis, downslanted palpebral fissures, and CVID-like phenotype [1-7]. KMT2A encodes a lysine methyltransferase with an integral role in transcriptional regulation of hematopoiesis [8, 9]. This case is first to report a KMT2A-associated Hodgkin lymphoma and additionally novel, its consistency with WSS [8-12]. ClinVar and GnoMad queries suggest his variant to be distinct in the clinical literature.
Currently, our patient is undergoing salvage immunotherapy, pending high-dose chemotherapy with BEAM/rituximab and autologous HSCT [13]. High-risk features of his lymphoma and immunodeficiency justify the plan for subsequent reduced intensity allogeneic HSCT [12, 14, 15]. This case emphasizes the need to improve understanding of the increased risk of lymphoma in CVID, its associated molecular pathways, and how these may impact treatment decisions.
References
