LAUSR

Editor The patient’s parents provided their written informed consent to participate in this study, in accordance with the European Society for Blood and Marrow Transplantation’s ethical framework (Clinical Investigation Centre: 334) and the tenets of the Declaration of Helsinki. Severe combined immunodeficiency (SCID) is characterised by absent or non-functional T cells. Most infants develop opportunistic infections and failure to thrive. Erythroderma may occur in patients with SCID and is caused by maternal T cells or autologous autoreactive T cells (Omenn Syndrome, OS). OS is furthermore characterised by lymphadenopathy, hepatosplenomegaly, hair loss, eosinophilia and elevated serum IgE. Here, we describe a 2-month-old girl who presented with erythroderma (Fig. 1) and axillary lymphadenopathies, followed by the development of hepatosplenomegaly with leucocytosis, lymphocytosis and eosinophilia over the next few months. While the serum IgE level was increased, IgM was initially normal. A skin biopsy was inconclusive, as it showed acute spongiform dermatitis with lymphohistiocytic infiltration of the dermis (Fig. 1) without any of the features required for other differential diagnoses such as atopic dermatitis, hyper-IgE syndrome, graft-versus-host-disease (which can be caused by maternal T cells) and Netherton’s syndrome. Lack of na€ıve T cells was noted, while NK and B cells were present (Table 1). The initially normal IgM levels started to drop at the age of 9 months, at which point a few maternal T cells were transiently present in the patient’s blood, indicating SCID. Failure to thrive, persistent cytomegalovirus infection and autoimmunity (idiopathic thrombocytopenic purpura) became apparent at 11 months of age and prompted the decision to perform haematopoietic stem cell transplantation (HSCT). The patient received reduced intensity conditioning prior to allogeneic HSCT from a 10/12 HLA-matched donor. Despite prophylaxis with acyclovir, cytomegalovirus reactivation was noted from day (D)12 post-HSCT onwards but was successfully controlled with foscavir. A norovirus infection was diagnosed on D64 post-HSCT. Combined enteral and parenteral nutritional support was required to obtain adequate nutrient intake. However, norovirus excretion persisted. Due to partial bone marrow failure, the patient was given a T-cell replete stem cell boost at the age of 33 months under immunosuppression (mycophenolate mofetil, cyclosporin and steroids) resulting in successful engraftment. However, after the reduction of immunosuppression, the patient developed grade III intestinal graft-versus-hostdisease and died at the age of 34 months. Post-mortem whole-exome sequencing revealed a homozygous mutation in the third exon of IL7R (rs193922641), which was confirmed by Sanger sequencing. This mutation corresponds to a homozygous p.C118Y mutation, which is known to cause defective IL-7Ra-expression and thus may explain the SCID with OS observed in our patient. Homozygous p.C118Y missense mutations have been described in two patients with SCID and in one patient with OS. Among all the genetic modifications found by whole-exome sequencing (WES), the IL7R mutations fit best with the patient’s phenotype, even though the initial presentation was unusual. This conclusion was further confirmed by a retrospective analysis of dried blood spots from the patient’s newborn screen revealing zero T-cell receptor excision circles (TRECs) per microgram of DNA.