Severe Combined Immunodeficiency Cutaneous Manifestations

Bone Marrow Transplantation (2001) 28, 227–233  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Severe combined immunodeﬁciency Cutaneous manifestations of maternal engraftment in patients with severe combined immunodeﬁciency: a clinicopathologic study

KS Denianke1, IJ Frieden2,3, MJ Cowan3, ML Williams2,3 and TH McCalmont4

1School of Medicine, 2Department of Dermatology, 3Department of Pediatrics, and 4Dermatopathology Section, Departments of Pathology and Dermatology, University of California, San Francisco, CA, USA

Summary: inheritance can be autosomal recessive or X-linked. These disorders are rare, with a frequency ranging from one in SCID is a heterogeneous group of disorders charac- 50000 to one in 500000 births.1 Clinical signs and symp- terized by defective T cell and B cell function. Eczema- toms commonly manifest by 6 months of age and include tous and morbilliform eruptions are common, and failure to thrive, oral thrush, candidal diaper rash, recurrent graft-versus-host disease (GVHD) due to maternal respiratory infections, cutaneous graft-versus-host disease engraftment has been documented. We sought to better (GVHD) and oral and genital ulcerations. The nonspecific characterize SCID-related cutaneous disease observed clinical findings and the significant degree of variability prior to BMT and to compare the eruption to conven- among patients often complicate and delay the diagnosis. tional GVHD. Medical records of 51 patients with SCID The profound lack in immune function leads to infections treated between 1982 and 1999 were reviewed. Ten of usually fatal in infancy unless the immune system can be 51 (20%) had rash and evidence of maternal reconstituted.1 Currently, hematopoietic stem cell trans- engraftment prior to BMT (study group). Eleven of 51 plantation from a variety of sources including bone marrow, (22%) had no rash or evidence of engraftment pre-BMT peripheral or umbilical cord blood is the primary modality but developed GVHD following transplant (control of treatment of SCID,2 although the early results of gene group). Skin biopsies were available for review for 8/10 therapy are encouraging.3 of the study group and for 8/11 of the control group. The major cutaneous manifestations of SCID are skin Cutaneous findings consisted of a scaling, erythematous and mucosal infections, eczematous rashes and GVHD. maculopapular eruption spread widely over the trunk Patients with SCID are frequently engrafted with transpla- and extremities, with near-erythroderma in some centally-derived maternal T lymphocytes. Although patients. Microscopically, biopsies from the study group maternal T cells in SCID rarely induce lethal, systemic, differed significantly from controls. Key differences р multiorgan GVHD, cutaneous manifestations of GVHD can included parakeratosis (P 0.01), psoriasiform hyper- be striking. Maternal engraftment may also be asymptom- plasia (P р 0.04) and spongiosis (P р 0.04). The derma- atic.4 It has been postulated that maternal T cells can pre- topathologic findings of transplacental GVHD differ vent engraftment of bone marrow transplants from nonma- from the pattern of post-transplant GVHD. A ‘psoriasi- ternal donors, in particular when HLA-mismatched form-lichenoid-spongiotic’ pattern with necrotic keratinocytes should trigger consideration of SCID and (haplocompatible) T cell-depleted transplants are used. maternal engraftment in the dermatopathologic evalu- Because engraftment is incomplete, in most instances maternal cells fail to protect the host against opportun- ation of eruptions of infancy. Bone Marrow Transplan- 5 tation (2001) 28, 227–233. istic infections. Keywords: severe combined immunodeficiency disease In contrast to the well-characterized histopathologic fea- (SCID); bone marrow transplant (BMT); graft-versus-host tures of GVHD due to BMT, those due to transplacental disease (GVHD); maternal engraftment maternal engraftment are less well studied. Some reports have identified features indistinguishable from post-transplant GVHD, but the reported microscopic features have not been consistent.6–8 We evaluated the clinicopathologic Severe combined immunodeficiency diseases (SCIDs) are characteristics of cutaneous GVHD in a group of SCID a heterogeneous group of genetic disorders characterized patients with evidence of maternal engraftment prior to by deficiency of both T and B cell functions. The mode of bone marrow transplant. We also sought to determine if the manifestations of GVHD in these patients were indeed distinct from the well characterized forms of GVHD asso- Correspondence: Dr IJ Frieden, Departments of Dermatology and Pedi- ciated with either bone marrow transplantation, the trans- atrics, University of California, San Francisco, 1701 Divisadero Street #340, San Francisco, CA 94115, USA plantation of other organs or the transfusion of non- Received 22 January 2001; accepted 18 May 2001 irradiated blood. Patients with SCID but no evidence of SCID and maternal engraftment KS Denianke et al 228 maternal engraftment pre-BMT who developed a rash after BMT but was blinded to the prior skin biopsy diagnosis. BMT were used as a control group. Chi-square statistical analysis was performed on the histopathological parameters.

Methods Results Patients Representative cutaneous lesions are described in Tables 1 The medical records of 51 patients with a diagnosis of and Table 2 and illustrated in Figure 1. The severity ranged SCID who received a BMT at the University of California, from fine erythematous maculopapular lesions involving San Francisco, Pediatric Bone Marrow Transplant Division the trunk and extremities to total erythroderma with alo- between 1982 and 1999 were reviewed. Ten of these pecia. In addition to rash, virtually all patients had oral patients were found to have evidence of maternal thrush and nonspecific symptoms of fever, cough, diarrhea engraftment and rash prior to BMT (group A). An and failure to thrive. Treatment regimens for cutaneous additional 11 did not have evidence of maternal lesions ranged from topical creams and steroids to systemic engraftment or a rash pre-BMT but developed rash post immunosuppression. Conditioning protocols ranged from BMT (group B).Two patients were found to have evidence none to combinations of systemic immunosuppressives. of maternal engraftment pre-BMT without rash and thus Seven of the eight patients in group A had rashes that were were excluded from the study. Four patients did not have unresponsive to multiple therapies but resolved after BMT. evidence of maternal engraftment pre-BMT but had a rash One patient had a rash that resolved with topical ketocona- pre-BMT. These patients did not have histopathology and zole therapy prior to BMT, but did not have a skin were thus also excluded. Twenty-four others, who had biopsy performed. neither engraftment nor rash before or after BMT, were also The histopathological results are shown in Table 3 and excluded from the study. illustrated in Figures 2 and 3. Of the eight patients in group A who had skin biopsies, only three had a previous histopa- Data acquisition thologic diagnosis of GVHD. Two had been diagnosed as subacute spongiotic dermatitis, two had vacuolar interface Patients of white, hispanic, native American, Middle East- dermatitis and one had a diagnosis of nonspecific derma- ern and Asian background were represented in this study. titis. Group B was utilized as a control group and of the After 1989, a diagnosis of maternal engraftment was made eight patients with skin biopsies, one had a prior histopa- based on variable number of tandem repeat (VNTR) analy- thologic diagnosis of GVHD, one had interstitial dermatitis, sis, also referred to as microsatellite analysis and/or in situ one had interface dermatitis, one had vascular ectasia and hybridization. VNTR probes give strong hybridization sig- four had superficial perivascular dermatitis. The parameters nals allowing for earlier detection of chimerism as well as that showed statistical significance were psoriasiform detection of small numbers of cells. Prior to 1989, methods hyperplasia (P Ͻ 0.04), parakeratosis (P Ͻ 0.01), spon- for detecting maternal engraftment included testing for giosis (P Ͻ 0.04), necrotic keratinocytes (P Ͻ 0.04) and blood group antigens, polymorphic blood proteins and kar- lichenoid infiltrate (P Ͻ 0.04). A perifollicular infiltrate yotyping. However, these tests are often not sufficiently was observed in 38% of patients in group A and in none sensitive to detect engraftment.9–11 Maternal engraftment of group B, which is borderline insignificant (P = 0.055). was diagnosed on clinical grounds, which in addition to The density of lymphocytes and other inflammatory cells skin eruption, included failure to thrive, hepatosplenome- did not show statistical significance between group A and galy and a lack of any other explanation for these findings group B. However, the very small number of patients in in the presence of the diagnosis of SCID. In addition, histo- these two groups may have resulted in a lack of statistical pathology with features of GVHD was also used as support- power to detect some of the differences that could exist ing evidence for cases prior to the late 1980s (3/10 in between them. group A). At diagnosis, the patients in group A had virtual absence of T and B cell numbers and function. The majority of Discussion patients in group A (70%) were T-B- with the remaining 30% being T−B+. Two of the T−B+ phenotypes were X- Our study indicates that maternal engraftment due to the trans- linked by familial inheritance pattern. In group B, 55% placental transfer of T cells is indeed a common phenomenon were T−B− and 45% were T−B+. Two of the T−B+ patients in patients with a diagnosis of SCID. Eighty-three percent of in group B were adenosine deaminase (ADA) deficient. those engrafted develop a skin eruption as a manifestation of Following medical record review, all available skin pathol- maternal engraftment that is clinically similar to that seen in ogy was reviewed for both groups. Pathology was available classic GVHD. However, the cutaneous histopathology in for 8/10 in group A and 8/11 in group B. The slides were maternally engrafted patients is distinct from the patients with read by a dermatopathologist who graded all subjects SCID who developed a rash post BMT (group B), and also according to standard histologic criteria. The pathologist distinct from classical cutaneous GVHD after transplant for was aware that all patients had a diagnosis of SCID and other diseases. Moreover, the definitive diagnosis of maternal– had received BMT. He was also aware of which group of fetal GVHD can be problematic because the clinical and histo- patients had a diagnosis of maternal engraftment prior to logical features are difficult to distinguish from other con-

Bone Marrow Transplantation SCID and maternal engraftment KS Denianke et al 229 Table 1 Clinical ﬁndings in transplacental maternal engraftment patients (group A)

Patient Age rash Age BMT Total Total CD3 CD3 % Morphology Conditioning Treatment and course onset (m) (y) lymphocyte (109/l) count (109/l)

1 1 0.2, 4.07 2.54 49 Diffuse erythematous scaly None Improved on steroids and i.v. 0.6, rash with oozing and Ancef prior to first BMT. 0.8 crusting beginning on chest Resolved post BMT and back, subsequently spreading to scalp, neck, arms and legs with severe involvement on palm, soles and buttocks 2 4 0.8 5.01 1.70 31 Generalized eczematous rash CY120 Responded to steroids and and erythroderma with thick ATG80 Velban prior to BMT but scaling in scalp and around 700 cGy recurred when stopped. mouth and nose Initially resolved with CsA and immunosuppression post BMT. Later continued to have chronic eczematous eruption intermittently 3 2.5 0.3 0.63 0.069 11 Diffusely xerotic skin, scaly None Unresponsive to creams and erythematous plaques in ointments given by mother flexural areas, eyebrows, prior to admission. Resolved scalp and diaper area post BMT with systemic and topical corticosteroids 4 1.5 0.4 3.41 1.67 59 Widespread flat-topped CY200 Resolved post BMT with lichenified, papules over ATG80 topical antifungal and topical trunk and extremities with corticosteroids minimal scale. Significant scaling with moderate erythema on scalp and central face 5 0 0.7, 12.8 8.49 65 Infiltrated lichenoid plaques Imuran No response to 5% lactic acid 1.2, on extremities and fine Prednisone and anionic base topical 1.8 atrophic scaly papules on ATG80 treatments. Minimal midtrunk. Complete loss of inflammation and scaliness with hair, including scalp, regrowth of scalp hair, eyebrows, eyelashes eyebrows and eyelashes post BMT 6 16 1.5 3.91 0.691 16 Fine erythematous ATG80 Response to CsA and maculopapular rash immunosuppression post BMT involving the face, body, extremities, including soles. Most prominent on cheeks 7 5 0.5 5.19 0.141 47 Fine erythematous CY200 Responded to ATG and maculopapular rash over ATG80 steroids post BMT trunk and extremities

8 1 0.8 0.75 0.008 1 Erythematous, scaly macular None Resolved after 2 months rash on face with raised Nizoral cream and shampoo; sharply demarcated lesions prior to BMT on neck. Erythematous rash around eyes and mouth 9 0 0, 2.19 0.460 21 Diffuse, desquamating Imuran Resolved with total body 0.2 erythematous rash consistent Prednisone irradiation and with toxic epidermal ATG80 immunosuppression post BMT necrolysis 10 0 0.3 5.45 4.5 45 Generalized scaling BU14 Resolved with erythematous rash CY200 immunosuppression post BMT ATG80

ATG80 = anti-thymocyte globulin 80 mg/kg; ATG90 = anti-thymocyte globulin 90 mg/kg; BU14 = busulphan 14 mg/kg; BU16 = busulphan 16 mg/kg; CY120 = cyclophosphamide 120 mg/kg; CY200 = cyclophosphamide 200 mg/kg; NA = not available. Normal ranges: Total lymphocyte count (2–14 × 109/l), total CD3 count (0.657–2.37 × 109/l), CD3% (53–84%).

Bone Marrow Transplantation SCID and maternal engraftment KS Denianke et al 230 Table 2 Clinical ﬁndings in post BMT patients (group B)

Patient Age rash Age BMT Total Total CD3 CD3% Morphology Conditioning Treatment and course onset (m) (y) lymphocyte (109/l) count (109/l)

11 14 1.1 0.21 0.02 1 Maculopapular erythematous None Resolved on steroids rash beginning on chest and spreading to face and extremities 12 1 0.1 0.32 0.003 1 Diffuse erythematous None Resolved on steroids papular eruption on face, trunk, and extremities 13 4 0.2 0.06 0 0 Erythematous maculopapular BU16 Self resolved rash on trunk CY200 ATG80 14 15 1.2 0.12 NA 4 Erythematous maculopapular CY120 Self resolved after mezlocillin rash on neck, axilla, groin ATG90 discontinued and trunk 700 cGy 15 4 0.3 2.62 0.224 20 Diffuse erythematous ATG80 Self resolved macular rash. Pruritic papular rash on lower extremities 16 12 1.3 2.33 NA 5 Morbilliform eruption CY120 Resolved with topical steroids involving neck, face, behind ATG90 and oral Benadryl ears, scalp and back 700 cGy 17 6 0.5 0.26 NA 15 Generalized erythematous ATG80 Resolved on systemic steroids eruption 18 6 0.5 0.06 NA 61 Scaly rash over distolateral CY200 Self-resolved aspect of lower extremities. ATG80 Red-purple macular rash over volar surface of forearms 19 2 0.1 0.55 0.006 1 Papular hypopigmented rash ATG80 Self resolved on scrotum and erythematous rash on face, trunk and extremities 20 12 0.9 1.8 0.006 1 Generalized erythematous CY200 Resolved with systemic macular rash ATG80 immunosuppression 21 3 2.1 0.92 0.091 76 Maculopapular rash on None Resolved with increased extensor surfaces of upper cyclosporine dose arms and face

ditions that can be seen in SCID patients, such as drug erup- The skin eruptions of GVHD due to maternal tions, exanthems or eczema. In addition, unlike most patients engraftment are clinically similar to those seen in patients with SCID who have profound lymphopenia, the peripheral with GVHD after BMT. These classic lesions have been blood lymphocyte count may be normal or even elevated in well characterized and involve an acute phase with morbil- transplacentally engrafted infants because of circulating liform erythema, papular dermatitis and diffuse erythro- maternal cells. derma. The face, neck, palms and soles are usually the Maternal engraftment secondary to transplacental trans- initial sites, prior to a generalized eruption. In severe cases, fer of T lymphocytes was observed in 24% (12/51) of all diffuse bullae or toxic epidermal necrolysis is observed. patients with SCID in this series, comparable to the pre- Rashes in our maternally engrafted patients spanned this viously reported figure of 25% by Thompson et al.12 It is morphological array. Cutaneous findings ranged from tran- possible that a greater percentage was engrafted and that the sient morbilliform to total erythroderma with alopecia. relative insensitivity of earlier methods precluded accurate Typically, these rashes were refractory to topical treatment detection. Although not utilized in our study, current tech- prior to BMT and resolved with systemic immunosuppres- nology involving locus-specific probes has enabled the sion shortly after BMT. retrospective testing of patients for engraftment post The histopathology of GVHD due to maternal BMT.10 engraftment differs significantly from that due to BMT. As

Bone Marrow Transplantation SCID and maternal engraftment KS Denianke et al 231 nostic confusion, since these are seen only rarely in classic GVHD. Lerner et al14 proposed the following grading scheme of GVHD: grade I, characterized by focal or diffuse vacuolar degeneration (of epidermal basal cells); grade II, characterized by vacuolar degeneration with dyskeratosis (keratinocyte necrosis); grade III, characterized by grade II changes plus subepithelial clefting; and grade IV, characterized by confluent epithelial necrosis. Spongiosis is not typically a prominent feature of GVHD due to BMT but, when present, is usually found in patients with grades III/IV disease, not grades I and II.15 Our findings of a statistically significant difference in the presence of spongiosis between group A and group B patients supports the conclusion that GVHD due to maternal engraftment has features which are distinct from that due to BMT. Graft-versus-host disease due to maternal engraftment should always be suspected in a neonate with erythroderma. The differential diagnosis of neonatal erythroderma is large including immunodeficiency disorders, infections, viral exanthems, drug eruptions, congenital psoriasis and several forms of ichthyosis.16 Microscopically, viral exanthems and certain drug eruptions can be difficult to distinguish from acute GVHD. Viral exanthems are characterized by a vacuolar interface pattern, but it is often subtle and necrotic keratinocytes are few compared to GVHD. Drug eruptions, especially drug-induced erythema multiforme (EM) is even more difficult as there are no well-defined histologic criteria to distinguish it from acute GVHD. Involvement of follicular epithelium is more common in GVHD but can be seen in EM. Fortunately, the clinical appearance of GVHD and EM are easily distinguished. Rarely, GVHD in neonates may be confused with ichthyosiform erythroderma, seborrheic dermatitis, atopic dermatitis, psoriasis, pityriasis Figure 1 (Patient 9) Generalized rash characterized by scaling and rubra pilaris, so-called Leiner’s disease, Langerhans cell erythema. histiocytosis, nutritional deficiencies of zinc, biotin, and essential fatty acids, and even widespread congenital syph- Table 3 Histopathology chi-square results ilis. However, clinicopathologic correlation is often sufficient to distinguish GVHD from these entities. Parameter Group A Group B P value The differentiation of GVHD caused by maternal (%) (%) engraftment and Omenn’s syndrome deserves special consideration. Omenn’s syndrome is an autosomal recessive Psoriasiform hyperplasia 88 38 0.038* form of combined immunodeficiency with a gene defect Parakeratosis 100 38 0.007* that has been mapped to chromosome 11.17 Typical features Spongiosis 88 38 0.038* Necrotic keratinocytes 88 38 0.038* include a widespread skin eruption, alopecia, lympho- Lichenoid infiltrate 88 38 0.038* cytosis, hepatosplenomegaly, lymphadenopathy, recurrent Follicular infiltrate 38 0 0.055 infections and failure to thrive. These features can also be Intradermal lymphocytes 88 100 0.302 seen in some cases of maternally induced GVHD. How- Eosinophils 50 12 0.106 ever, in Omenn’s syndrome the degree of eosinophilia, Histiocytes 25 12 0.522 lymphadenopathy and hepatosplenomegaly are usually 16 *Reaching statistical significance. more pronounced. Some reported cases of Omenn’s syndrome have had microscopic features which strongly resemble those of our maternally engrafted patients.7 In noted, GVHD secondary to maternal engraftment is charac- addition, many either did not mention or did not have docu- terized by psoriasiform hyperplasia with parakeratosis and mentation of maternal engraftment using current, more variable spongiosis, in contrast to the vacuolar interface sensitive methods of detection. Thus, some patients pattern observed in conventional GVHD, yet necrotic kera- reported as having ‘Omenn’s syndrome’ may actually have tinocytes (suggesting an element of keratinocytotoxicity) had maternally-induced GVHD. are identifiable in both diagnostic groups.13 The consistent Three of our patients had many features of Omenn’s syn- findings of psoriasiform hyperplasia and prominent spon- drome. Patient 10 presented with a total body erythematous giosis in particular are distinctive and can easily cause diag- rash, fever, hepatomegaly and eosinophilia at 1 month of

Bone Marrow Transplantation SCID and maternal engraftment KS Denianke et al 232

Figure 2 A low magnification view of the eruption associated with maternal engraftment shows slight psoriasiform epidermal hyperplasia, focal spongiosis and parakeratosis, and a fairly dense papillary dermal infiltrate. This ‘lichenoid-psoriasiform’ pattern contrasts distinctly to the pattern of conventional GVHD, in which the epidermis usually displays vacuolar alteration of the lower most epidermis in association with a sparse superficial dermal infiltrate.

Figure 3 Higher magniﬁcation reveals single necrotic keratinocytes with closely opposed lymphocytes, similar to the pattern of ‘satellite cell necrosis’ in conventional GVHD.

age. He was diagnosed with SCID in 1983, and laboratory drome is not necessarily excluded since none had specific studies available at this time may not have been sensitive gene testing for Omenn’s syndrome. enough to detect maternal engraftment. Patient 7 presented The explanation for the differences in cutaneous GVHD at age 5 months with a fine erythematous maculopapular in group A and classical GVHD is probably multifactorial. rash over his trunk and extremities, lymphadenopathy, One difference may be the limited T cell receptor diversity hepatomegaly and eosinophilia, but was found to be of transplacentally acquired maternal T cells in SCID. maternally engrafted by VNTR analysis. Patient 2 Thus, Knobloch et al5 demonstrated that maternal T cells presented at 4 months with a generalized eczematous rash express a profoundly reduced heterogeneity in their TCR accompanied by lymphadenoapthy, hepatosplenomegaly, repertoire by using a panel of mAb specific for TCR V and eosinophilia and was also found to be maternally region epitopes. This lack of heterogeneity may correlate engrafted by VNTR analysis. In spite of conclusive evi- with the distinct histopathological findings in those patients dence of maternal engraftment in patients 2 and 7 and high receiving maternal T cells transplacentally, as opposed to clinical suspicion in patient 10, coexistent Omenn’s syn- via BMT. Similarly, T cell functions may be limited, corre-

Bone Marrow Transplantation SCID and maternal engraftment KS Denianke et al 233 sponding to the number of maternal cells that cross the pla- Epstein–Barr virus-derived B cell lines. J Immunol 1983; 130: centa. Unlike the better documented and more abundant 2493–2495. presence of fetal lymphocytes in the circulation of the 5 Knobloch C, Goldman S, Friedrich W. Limited T cell receptor mother, it has been suggested that only trace amounts of diversity of transplacentally acquired maternal T cells in sev- maternal cells enter the fetus. Thus, the distinct features of ere combined immunodeficiency. J Immunol 1991; 146: 4157–4164. cutaneous GVHD in patients with maternal engraftment 6 Alain G, Carrier C, Beaumier L et al. In utero acute graft- pre-BMT may be due to functional characteristics of the T versus-host disease in a neonate with severe combined cells or a functionally limited repertoire of T cells when immunodeficiency. J Am Acad Dermatol 1993; 29: 862–865. these patients are engrafted transplacentally. 7 Appleton A, Curtis A, Wilkes J, Cant A. Differentiation of The early diagnosis of SCID is critically important since materno–fetal GVHD from Omenn’s syndrome in pre-BMT early BMT can provide a definitive cure and avoid severe patients with severe combined immunodeficiency. Bone morbidity or mortality from the immunodeficiency itself. Marow Transplant 1994; 14: 157–159. The clinician should consider the diagnosis of SCID when 8 Farrell A, Scerri L, Stevens A, Millard L. Acute graft-versus- confronted with a widespread cutaneous eruption and asso- host disease with unusual cutaneous intracellular vacuolation ciated pathology as described above. This study highlights in an infant with severe combined immunodeficiency. Pediatr Dermol 1995; 12: 311–313. the diagnostic value of skin histopathology in infants with 9 Gatti R, Nakamura Y, Nussmeier M et al. Informativeness widespread rashes along with other symptoms such as of VNTR genetic markers for detecting chimerism after bone thrush, diarrhea and failure to thrive. Recognizing the clin- marrow transplantation. Dis Markers 1989; 7: 105–112. icopathologic findings described in this study may aid in 10 Katz F, Malcom S, Strobel S et al. The use of locus-specific earlier diagnosis of SCID with maternally induced GVHD, minisatellite probes to check for engraftment following which in turn can lead to earlier treatment. allogeneic bone marrow transplantation for severe combined immunodeficiency disease. Bone Marrow Transplant 1990; 5: 199–204. Acknowledgements 11 Tachinami T, Koizumi S, Yachie A et al. Immune status in two brothers with Omenn’s syndrome: no discernible chimerism on FACS analysis using a monoclonal antibody specific Mort Cowan, MD would like to acknowledge the NIH RO1 for a maternally restricted HLA antigen. J Pediatr Hematol AI28339 and March of Dimes FY95–0954 grants. Oncol 1990; 12: 343–350. 12 Thompson LF, O’Connor RD, Bastian JF. Phenotype and function of engrafted maternal T cells in patients with severe References immunodeficiency. J Immunol 1984; 133: 2513–2517. 13 Parkman R, Rappeport J, Rosen F. Human graft versus host 1 Buckley R, Schiff R, Schiff S et al. Human severe combined disease. J Invest Dermatol 1980; 74: 276–279. immunodeficiency: genetic, phenotypic and functional diver- 14 Lerner K, Kao G, Storb R et al. Histopathology of graft-vs- sity in one hundred eight infants. J Pediatr 1997; 130: 378– host reaction (GvHR) in human recipients of marrow from 387. HL-A-matched sibling donors. Transplant Proc 1974; 4: 2 Dror Y, Gallagher R, Wara DW et al. Immune reconstitution 367–371. in severe combined immunodeficiency disease after lectin- 15 Massi D, Franchi A, Pimpinella N et al. A reappraisal of the treated, T-cell depleted haplocompatible bone marrow trans- histopathologic criteria for the diagnosis of cutaneous plantation. Blood 1993; 8: 2021–2030. allogenic acute graft-vs-host disease. Am J Clin Pathol 1999; 3 Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G et al. 112: 791–800. Gene therapy of human severe combined immunodeficiency 16 Hoeger P, Harper J. Neonatal erythroderma: differential diag- (SCID)-X1 disease. Science 2000; 288: 669–671. nosis and management of the ‘red baby’. Arch Dis Child 1998; 4 Geha R, Reinherz E. Identification of circulating maternal T 79: 186–191. and B lymphocytes in uncomplicated severe combined 17 Villa A, Santagata S, Bozzi F et al. partial V(D)J recombi- immunodeficiency by HLA typing of subpopulations of T nation activity leads to Omenn syndrome. Cell 1998; 93: cells separated by the fluorescence-activated cell sorter and of 885–896.

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