Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

Abstract

Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH.

Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients

“…Plasma was analyzed for total and allergen-specific IgE (food or mite mix) (26). PBMCs were also collected from patients with recessive mutations in CYBB, STK4, or UNC13D or hemizygous CD40LG or SH2D1A mutations who had previously undergone HSCT (Table 3) (62)(63)(64).…”

“…It was possible that some of the impairments in lymphocyte differentiation in transplanted DOCK8-deficient patients were unique to DOCK8 deficiency or a general consequence of HSCT in PID. To differentiate between these possibilities, we examined lymphocytes in 8 additional PID patients who underwent HSCT due to loss-of-function mutations in UNC13D (n = 2), STK4 (n = 2), CYBB (n = 2), CD40LG (n = 1), or SH2D1A (n = 1) ( Table 3) (62)(63)(64). Time after HSCT ranged from 5 to 84 (mean 44.5) months ( Table 3).…”

Adaptive reprogramming of NK cells in X-linked lymphoproliferative syndrome

“…NK-or T-cell function was assessed by 51 Cr-release cytotoxicity assay and by CD107a externalization assay using K562 target cells. 7 Detailed protocols, reagents used in this study, and gating strategy for NK-cell phenotype are described in supplemental Methods (available on the Blood Web site).…”

Two Brothers with Atypical UNC13D-Related Hemophagocytic Lymphohistiocytosis Characterized by Massive Lung and Brain Involvement

“…Moreover, in many cases of atypical FHL, the peripheral signs of HLH may be completely absent, making the diagnosis even more difficult to achieve. In a recent paper, Gray et al reported on a case of late-onset FHL3 in which the clinical presentation was characterized by growth arrest, inflammatory arachnoiditis, and dysgammaglobulinemia, without any signs of HLH ( 10 ). Similarly, the hypomorphic A91V variation has been recently described in association with atypical late-onset HLH in a patient with neuromyelitis optica ( 27 ).…”

“…FHL usually presents within the first 2 years of life ( 9 ). However, the increasing awareness of the signs and symptoms of HLH and the better comprehension of the genetic basis of the disease allow the identification of FHL in patients presenting beyond infancy and sometimes before the development of the HLH ( 10 ). Atypical presentations have been reported in adolescents and even in adults, characterized by milder and often recurrent HLH episodes and prolonged survival in the absence of hematopoietic stem cell transplantation (HSCT), unusual in patients with the typical disease.…”