X-Linked Lymphoproliferative Syndrome Presenting as Adult-Onset Multi-Infarct Dementia

Abstract

Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is $11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment. The patient had 2 brothers; 1 died of aplastic anemia at age 13 and another died of diffuse large B-cell lymphoma in his sixties. Exome sequencing of the patient and his older brother identified a novel hemizygous variant in SH2D1A (c.35G>T, p.Ser12Ile), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Molecular modeling and functional analysis showed that this variant had decreased protein stability, similar to other pathogenic missense variants in SH2D1A. The family described in this report highlights the broadly heterogeneous clinical presentations of XLP and the accompanying diagnos-tic challenges in individuals presenting in adulthood. In addition, this report raises the possibility of a biphasic distribution of XLP cases, some of which may be mistaken for age-related malignancies and autoimmune conditions.

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor

“…Despite surviving life-threatening childhood manifestations and being maintained on lifelong IVIG therapy, he suffered from neurologic deficits and progressive lung disease and eventually died of lymphoma. Similarly, recent published cases of XLP1 patients either do not survive initial childhood manifestations of XLP1 or succumb to complications in mid-adulthood [ 10 , 12 , 18 , 20 – 27 ]. This remains an important point to emphasize during shared decision making with newly diagnosed patients with XLP1 who are eligible for HSCT.…”

“…We reason that his maintenance IVIG and hydrocortisone provided immunomodulatory effects that aided in his surprising recovery. As exemplified by this case, the majority of reported CNS vasculitis (8/10) in XLP1 has no identifiable infectious trigger [ 20 ]. This suggests that CNS vasculitis associated with XLP1 has an intrinsic trigger leading to lymphocytic infiltration into cerebral vessels.…”

“…Our case also represents a rare patient with untransplanted XLP1 who lived into mid-adulthood. Literature review revealed six additional untransplanted XLP1 patients who survived into their forties ( Table 2 ) [ 20 – 22 ]. Of the five cases that looked at protein, all had mitigating factors (i.e., genetic reversion or unstable yet functional protein) that led to residual protein expression.…”

“… ∗ The two cases from Blackburn et al [ 20 ] were brothers. # Genetic reversion is defined as a secondary mutation that counteracts the effects of the primary mutation, thereby reversing the phenotype back to wild type.…”

Preimplantation Genetic Testing for a Chinese Family With X-Linked Lymphoproliferative Syndrome Type 1

“…X-linked lymphoproliferative disease (XLP) is a rare life-threatening immunodeficiency disorder with an estimated incidence rate of 1–3 per million among males ( Blackburn et al, 2019 ). XLP is characterized by a severely dysregulated immune response following infection by Epstein-Barr virus (EBV).…”