ABSTRACT
Human herpesvirus 6 (HHV-6) is a widely spread DNA virus that is ubiquitous and persistent with primary infection occurring in early childhood, with reactivation of the infection a common phenomenon in severely immunocompromised hosts, including hematopoietic stem cell transplant (HSCT) patients, influencing morbidity and mortality. A wide spectrum of clinical presentations is reported in the literature with HHV-6 reactivation including post-transplant limbic encephalitis (PALE). We report the unusual case of a 6-year-old female 107 days postallogenic HSCT due to transfusion dependent beta thalassemia major who developed acute cerebellitis with secondary supratentorial hydrocephalus that required invasive surgical intervention. In addition to accompanying imaging findings, the patient tested positive for HHV-6 by PCR from both serum and CSF samples and demonstrated dramatic improvement with the institution of steroid therapy in addition to ganciclovir treatment. The availability of rapid diagnostic measures in addition to a multidisciplinary approach is crucial to manage HHV-6 encephalitis and associated complications in HSCT patients.
Subject(s)
Hematopoietic Stem Cell Transplantation , Herpesvirus 6, Human , Hydrocephalus , Roseolovirus Infections , Humans , Herpesvirus 6, Human/isolation & purification , Hematopoietic Stem Cell Transplantation/adverse effects , Female , Hydrocephalus/etiology , Hydrocephalus/surgery , Child , Roseolovirus Infections/virology , Roseolovirus Infections/diagnosis , Roseolovirus Infections/complications , Roseolovirus Infections/drug therapy , Antiviral Agents/therapeutic use , Encephalitis, Viral/etiology , Encephalitis, Viral/virology , Encephalitis, Viral/diagnosis , Encephalitis, Viral/drug therapy , beta-Thalassemia/complications , beta-Thalassemia/therapy , Immunocompromised HostABSTRACT
We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2(IL2RG):c.820_823dup p.Ser275Asnfs*29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of "X-linked recessive Mendelian susceptibility to mycobacterial disease" (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.
ABSTRACT
Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbß3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as "Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem." The defects are also associated with infections, designated as "LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency." The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed "leukocyte adhesion deficiency, type III" (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins ß1, ß2, and ß3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.