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Cutaneous Lesions in Severe Combined Immunodeficiency: Two Case Reports and a Review of the Literature C. Postigo Llorente, M.D., J. Ivars Amoros, M.D., F. J. Ortiz de Frutos, M.D., J. R. Regueiro, M.D., R. Llamas Martin, M.D., A. Guerra Tapia, M.D., and L. Iglesias Diez, M.D. Department of Dermatology and Immunology, Hospital 12 de Octubre, Madrid, Spain _
Abstract: Two patients with severe combined immunodeficiency (SCID) in whom cutaneous lesions were the first clinicai feature were studied. Neither the morphology nor the histology of the iesions was uniform, although we have noted some common findings that can, in subsequent cases, iead us to suspect SCID. The immunologic defects were not uniform, representing the two poles of the spectrum of SCID. We believe that early recognition of the skin lesions is very important, since the patient's life expectancy can be increased by a bone marrow transplantation (1).
Among the primary immunodeficiencies, severe combined immunodeficiency (SCID) consists of a heterogeneous group of diseases characterized by a cell-mediated and humoral deficiency (2). Two patterns of inheritance have been identified since its initial description (3), X-linked and autosomal recessive, although sporadic cases have also been reported (2). The disorder begins in the first few weeks of life, usually with clinical fmdings derived from functional alterations of T cells and with persistent oral candidiasis the most common feature. The patients are susceptible to severe viral and bacterial infections, opportunistic infections, and graft-versushost disease (GVHD) (2-4). Although cutaneous lesions in SCID are commonly described in textbooks of dermatology and pediatrics, if those resulting from infections and GVHD are excluded, reports of
Address correspondence to C. Postigo Llorente, M.D., Department of Dermatology, Hospital 12 de Oclubre, Madrid 28041, Spain.
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other skin lesions in the literature are rare. Therefore, we report two new cases of SCID with cutaneous iesions with the purpose of contributing to the disease description and clarifying their significance. CASE REPORTS Patient No. I
This giri was the fourth child of nonconsanguineous parents, born at term with a weight of 3200 g. She was healthy until age 20 days, when erythematous lesions with a slight desquamation were noted on her face, spreading to her trunk and limbs in a few days. When we saw the patient one month later, she was febrile, with rhinorrhea, irritable cough, dyspnea, anorexia, and little weight gain. Erythematous macular and papular lesions were present on the cheeks and chin, forming pink to slightly yel-
Llorente et al: Cutaneous Lesions 315
low, sharply marginaled. eczematous plaques with crust scale (Fig. 1). Isolated papuloerythematous lesions, similar to those on the face, were present on the abdomen, knees, and elbows. There was no alopecia or lesions on the mucous membranes. Family history was relevant in that a brother who had died at 2 months of age from sepsis due to coagulase-positive staphylococci had been examined at age 1 month for cutaneous lesions that, according to the parents, were similar to those of our patient. Further physical examination revealed left otitis. small occipital and inguinal adenopathy, and hepatomegaly of 2 cm without splenomegaly. Neurologic examination was normal. Laboratory test results were white blood cell count 27,000/mm\ with 839^ eosinophils (23,074/ mm-^), 10% neutrophils, 5% lymphocytes, and 2% monocytes. Red blood cell series and platelets as well as urinalysis were normal. Blood chemistry showed a slightly low protein, 4.8 g/dl. associated with an elevation of a, globulins (14.7%), and a de-
crease of 7 globulins (7.3%). Cerebrospinal fluid studies were nonnal. No thymic shadow was seen on chest roentgenogram. Gastrointestinal series and skeletal radiographs were normal. Immunologic studies showed a normal quantification of B lymphocytes, and serial determination of immunoglobulins indicated that there was a progressive decrease in IgG level (310, 240, 210 mg/dl); IgE was 15 IU/ml; IgA and IgM were absent. Isohemagglutinins were not detected and autoantibodies were negative. Complement values C3, C4, and CH50 were normal, as were serum opsonic capacity and generation of C5a. No serum inhibitors of chemotaxis were found. The numbers of T lymphocytes and subpopulations of helper and suppressor cells were normal. Proliferative response to phytohemagglutinins was within normal limits, but no response was detected in mixed lymphocyte culture. Determinations of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) were normal. The HLA typing was done in the patient's father, with a genotype of A30, A32, B18, B14, BW6, CW5. The mother's genotype was Al, A28, B8, BW6, CW7. and the child's was A32, A28, B14, BW6, sharing three paternal haplotypes and two maternal ones. Circulating maternal cells were not detected in the patient. In the first days of hospitalization, cutaneous biopsy specimens taken from abdominal and knee lesions showed a hyperkeratotic epidermis with foci of parakeratosis and moderate irregular acanthosis; there were exocytosis and spongiosis, forming intraepidermal vesicles filled with eosinophils (Fig. 2). The upper and middle dermis contained a diffuse but predominantly perivascular infiltrate of eosinophils, histiocytes, and lymphocytes (Fig. 3). Immu-
Figure 1. Pink to slightly yellow, sharply marginated, eczematous plaques with crust scale, located symmetrically on the central face.
Figure 2. Hyperkeratosis and irregular acanthosis with foci of spongiosis and an intraepidermal vesicle. (Hematoxylin & eosin; magnification 100x.)
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diac failure. She died of acute hepatic failure when she was 95 days old. at which time her white blood cell and eosinophil counts had become normal. Pathologic studies showed a hypoplastic thymus gland, with lymphoid depletion and absence of Hassal's corpuscles. The lymph nodes, spleen, and intestine contained no lymphoid follicles and plasma cells; however, some discrete eosinophilic infiltrates were seen. The changes in the skin were similar to those detected in the biopsy specimens but with less intensity. The liver had an increased volume with some necrotic areas, scarce eosinophilic infiltrates, and numerous intranuclear inclusion bodies in its hepatocytes, suggesting a hepatitis from herpes simplex virus. Patient No. 2
Figure 3. Derma! infi!trate of eosinophils, histiocytic cells, and lymphocytes. (Hematoxy!in & eosin; magnification 400 X.I
nohistochemical sludy of paraffin-em bedded sections identified the dermal histiocytic cells as typical macrophages. which expressed reactivity with MAC 387. HLA-Dr (a), and MB3; iymphoid cells were positive with T cell markers UCHLl and MTi. Furthermore, MBl was also positive and no reactivity was shown with L26. Therefore they were T lymphocytes. In the epidermis, keratinocytes were stained with MAC 387 and focally expressed HLA-DR; a decrease of intraepidermal stain with S-IOO was observed, and the same pattern as the dermal lymphocytes was demonstrated by inflammatory cells, thus confirming that they were T lymphocytes. During hospitalization the patient's skin lesions remained stable. She had various infections from which different organisms were isolated: urinary tract infection by Klehsieila, conjunctivitis by Haemophilus influenzae, acute gastroenteritis by 5a/monella enteritides, and upper respiratory infection associated with bilateral otitis by coagulase-positive Staphylococcus. Blood cultures were repeatedly negative. Later the child had progressive weight loss with worsening of her general condition and signs of car-
This girl was the second daughter of healthy nonconsanguineous parents and had no relevant family history. She was born at 36 weeks" gestation, weighing 2430 g (2nd percentile). She was breastfed until 16 days, when she developed orai candidiasis and erythematous lesions on her face and diaper area that spread to the whole body. Two days later she had a fever of 38°C. When she was hospitalized at age 21 days, a generalized maculopapular rash with desquamation was noted, being most marked on the ears, scalp, and in the nasolabial folds. Physical examination was normal and laboratory findings were as follows: white blood cell count 7270/mm^ with 64% neutrophils. 9% lymphocytes, and 14% eosinophils (1107/mm-'); platelet count was 688.000/mm^. Results of urinalysis. renal function tests. liver functions tests, and chest radiographs were normal. A smear of pharyngeal secretions, blood cultures, and cultures for enterovirus from the pharynx, urine, and stool were negative. On the second day after admission, her temperature returned to normal and the skin lesions began to fade, with desquamation. During the following two months, until her second admission, she had three outbreaks of cutaneous lesions that started as a maculopapular rash and later formed erythematous, sharply marginated, symmetrically located plaques (Fig. 4) on the trunk, faee, and extensor surface of the limbs. The lesions were eczematous. with small vesicles at their periphery. The scalp appeared to be covered by greasy scales with sparse hair (Fig. 5); the palms and soles were spared. The lesions began to desquamate on day 5 to 6, with large desquamative scales
Llorente et al: Cutaneous Lesions
Figure 4. Sharply marginated, pink, eczematous plaques on the legs.
in the nasolabial folds and retroauricular areas (Fig. 6). Histologic examination of the epidermis demonstrated foci of hyperkeratosis with parakeratosis, irregular acanthosis, and spongiosis with exocytosis of chronic inflammatory cells. Occasionally, necrotic keratinocytes and a phenomenon of satellitosis were also noted. In the papular dermis there was edema, and a diffuse though predominantly perivascular infiltrate of histiocytes, lymphocytes, and some eosinophils. Immunohistochemical studies on paraffin-embedded sections showed similar results to those of patient no. 1, except that no expression of HLA-DR was observed on the surfaces of the keratinocytes. The outbreaks of cutaneous lesions were associated with two- to three-day self-limited febrile episodes, during which time the patient continued to have oral candidiasis. When she was readmitted, she had a generalized desquamation, lesions suggestive of foUiculitis, and right external otitis. On physical examination, she had retarded growth with weight and height below
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Figure 5. Seborrheiform, eczematous dermatitis of the scalp with crust scale. The hair appears sparse.
Figure 6. Eczematous erythroderma with large desquamative scales predominantly around the mouth.
the third percentile, and iaterocervical, occipital, and bilateral axillary adenopathy. Hepatomegaly was 4 cm and splenomegaly 3 cm. Laboratory data revealed a white blood cell count of 10,660/mm"' with 25% neutrophils, 12% lymphocytes, 12% monocytes, and 29% eosinophiJs (3029/mm^); hemoglobin 10.5 g/dl; hematocrit 34%
318 Pediatric Dermatology Vol. 8 No. 4 December 1991 with normal erythrocytic index; platelet count 390,000/mm; and hepatic enzymes of GGT, 71 IU/ L, serum glutamic oxaloacetic transaminase, 352 IU/L, and serum pyruvic oxaloacetic transaminase. 246 IU/L. Urinalysis v^as normal and there was no evidence of thymic shadow on chest radiograph. Puncture aspiration of a lymph node produced a discrete quantity of lymphoid tissue in which histiocytic cells were predominant, with scarce lymphocytes of mature aspect and few eosinophils. Immunologic studies showed hypogammaglobuJinemia and a significant decrease in the population of T3 lymphocytes with reduced proliferative response to mitogens and allogenic cells. There was only response to interleukin-2. In addition, 549f of Til lymphocytes did not express T4 and T8. determination of IgE was 76 IU/mi, and ADA and PNP were normal. An HLA typing of the patient and her parents did not show circulating maternal lymphocytes. Her father's immunologic studies were normal.
begins in the first weeks of life with eczematous lesions that usually appear first on the face and rapidly generalize. These are accompanied by lymphadenopathy, hepatomegaly and, less frequently, splenomegaly. The evolution is fatal, with diarrhea and failure to thrive. Eosinophilia and a prominent infiltration of lymph nodes by histiocytic cells are characteristic. In 1972 Barth et al (10) proposed the existence of a primary immunodeficiency in Omenn's syndrome, which later was characterized as SCID (11,12). Therefore, al! the cases described as Omenn's syndrome may have been SCID. and cutaneous lesions would be the most remarkable clinical feature. Similar disorders had been reported before 1965; that is. patients with Leiner's syndrome, which includes diarrhea, failure to thrive, and generalized seborrheic dermatitis (13). Some of these children died (14,15). and in 1988 Glover et al (16) concluded that this syndrome was highly suggestive of immunodeficiency, although not of a specific kind. One of their patients had SCID.
With the diagnosis of SCID, the patient was scheduled to undergo a bone marrow transplant, but on day 20 after admission she was transferred to an intensive care unit because of respiratory distress. Numerous consolidations were seen radiographically in both hemithoraces. The eosinophilia disappeared and she developed severe anemia; the skin showed xerosis with discrete desquamation during this time. The patient died of severe hypoxia 40 days after admission. Pneumonia from Pneumocystis carini was suspected, but autopsy was not performed.
We reviewed the literature since the first description of SCID (3), and found 32 patients with skin lesions that were due to neither infections nor GVHD (9-12.14,16-30); 21 of them were published as Omenn's syndrome. Ten chiidren had familial antecedents of a suggestive feature of SCID, but cutaneous lesions appeared in only 5 of these families (9.10.27.28). The lesions, which began between the first and twenty-first days of life, were the initial sign of the disease in all cases. In 14 patients they appeared widespread, in the form of a desquamative erythematous rash (11,12,16,17.22). Less frequently, the rash was morbilliform (18) or vesiculopapular (12). In nine patients the lesions began on the head, resembling a seborrheic dermatitis or eczema (9.20.2].23.26.28.30). and in a few the lesions began on the skin folds or in the diaper area (9.14,26). They generalized in all the children, although the involvement of palms and soles was rare (9,22). Alopecia was common, being present in 14 patients (11,12,23,24.26,29,30), and appearing either at the onset or later, progressively affecting the scaip, eyelashes, and eyebrows. Only one patient, described by Omenn (9), had lesions on the mucosa.
DISCUSSION Severe combined immunodeficiency comprises a group of congenital and usually hereditary diseases characterized by a deficiency of both T cell and B cell systems, whether or not there is lymphopenia and/or absent immunoglobulin (2). In most cases the molecular basis of the disorder is unknown. In some, however, various anomalies at the level of the lymphocyte membrane have been identified, such as the lack of expression of HLA class I and II molecules (bare lymphocyte syndrome) (5-7) and enzymatic defects (8,9). In the United States, half of the autosomal recessive cases involve a deficiency of the enzyme ADA (4). If the dermatologic manifestations secondary to infections and GVHD in patients with SCID are excluded, we find other lesions, which were first described by Omenn in 1965 (9). Omenn's syndrome
When fuily developed, the morphology of the cutaneous lesions was not uniform in all patients. In 33% the iesions evolved to an erythroderma with a progressive infiltration of the skin, especially on the face and skin folds of the limbs, having a pachydermal aspect (20,23,24,26,27). In the rest, lesions appeared as a papular rash (9,12,30) or were simply
Llorente ei al: Cutaneous Lesions 319 described as an erythematous rash. Generalized desquaniation of variable intensity was present in all children, most notably on the face and scalp, which appeared covered by thick scales and crusts (9,12,14). During the course of the disease, most children had vesicles or exudative areas, sometimes fissured, showing an eczematous aspect of the lesions, especially at the flexures of the iimbs. In our two patients, the skin lesions also appeared at the beginning of the disease, and tended to spread from the head to the rest of the body, although in patient no. 1 isolated ones were located on the limbs and abdomen. We did not observe pachyderma and infiltration at the level of skin folds, perhaps because, when described, these are late signs (23,26). The common and most striking finding in both patienis was the clinicaJ aspect of the lesions, which, although having the color and distribution of a seborrheic dermatitis, were eczematous and covered by scales and crusts, especially on the face and scalp. Therefore, we could not accept these as typical of atopic or seborrheic dermatitis. The histologic findings described in 22 patients (9-12,14.16.19-21.23,24,26-28.30) were not specific. In the dermis there was a predominantly perivascular inflammatory infiltrate of histiocytic cells, which, in some cases, had the same antigenic and enzymatic profile as Langerhans cells (28), but without Birbeck granules (20,21.24.30). In other cases, the profile was similar to macrophages (27); in addition to these cells, eosinophils in variable numbers and T lymphocytes were present. The epidermis contained foci of hyperkeratosis and exocytosis of the lymphocytes corresponding to a phenotype of suppressor T cells (27). Some patients demonstrated histologic data compatible with GVHD (27,31), but this finding was not constant (19,28). As in GVHD (32,33), there was a decrease in the number of Langerhans cells T6 (+) and an expression of HLA-DR antigens by keratinocytes (27). These facts are not specific to GVHD because some dermatoses with exocytosis of mononuclear cells may have the same characteristics (34,35). We also observed this nonspecific histology in our patients, although in patient no. 1 eosinophils were predominant in the dermal infiltrate. Immunohistochemicai studies have identified the histiocytic cells as macrophages and the intraepidermal lymphocytes as T lymphocytes. We have not found the characteristic histologic findings of GVHD, The cutaneous lesions preceded a syndrome characterized by a progressive appearance of hepa-
tomegaly in all patients, and splenomegaly and adenopathy in 26 patients (89%). All had peripheral eosinophilia with a cell count between 1898 (12) and 20,800/mm (20); IgE level was elevated in 16 patients (11,18-20,22,24-28.30). The course of the disease, with many infections, failure to thrive, diarrhea, and death, was similar to that of the classic SCID (2). In 14 patients, recurrent oral candidiasis was observed from the onset of the syndrome (9,12.14,16,18,20,22,24,28-30). Our patients' disease also began with skin lesions and progressively deveioped the rest of the ciinicai picture. Both had eosinophilia when the lesions were most evident, but the eosinophil count had become normal by the final stage of the disease; at that time patient no. 2 did not have cutaneous lesions, and in patient no. 1 the intensity of the lesions had considerably decreased. We think that the latler had a syndrome identical to that described by Omenn in 1965. In patient no. 2 we could not demonstrate the infiltration of the lymph nodes by histiocytic cells, but the clinical findings were very similar to those in Omenn's syndrome. The basis of the immunologic defect is not clear, and as in patients with classic SCID. the initial change can be seen at various stages of the lymphocytic differentiation, leading to the presence of immature lymphocytes in peripheral blood (20,22.28,36). On several occasions, a deficiency of lymphocytic 5 nucieoiidase enzyme was found (18,20.21,24-26). but it was not the rule (23,26,27). Il seems to refiect an immature state of iymphocyte differentiation or an imbalance in the proportion of lymphocyte subsets (18,25,37.38). Our two patients represent the two poles of the spectrum of SCID. In patient no. 1, the finding of Til lymphocytes that did not express T4 or T8, together with the proliferative response to interleukin-2. means that the alteration was located in immature lymphocytes (thymocytes) (39). The cutaneous lesions and other manifestations occurring in these patients have been interpreted as an abnormal immune response to an antigenic stimulus, leading to a proliferation of histiocytic cells, eosinophils, and T lymphocytes (19.25,28). Initially, the cutaneous lesions appear when there is a certain capacity for immunologic response. However, with progressive immunologic deterioration, they decrease or even disappear, as occurred in our patients. Some authors proposed the hypothesis of GVHD in relation to maternal ceils (10,11,25,27), but circulating maternal cells have never been
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found in these patients. When the histology of GVHD is seen it is possible that it has been mediated by maternal autocytotoxic celis, which are not inhibited by the suppressor T lymphocytes of the child, owing to an immunoiogic deficiency (40). We would like to emphasize the great importance of early diagnosis of SCID, since correct medical management can improve the patient's life expectancy. The dermatologist should consider this diagnosis when confronted with an infant with the types of cutaneous lesions we have described, since they can be the first clinical manifestation. Even if there are no familial antecedents of SCID, it shouid be suspected, especially when the cutaneous lesions are accompanied by eosinophiiia and oral candidiasis. REFERENCES 1. Reinherz EL, Geha R. Rappaport JM. et ai. Immune reconstitution in severe combined itnmunodeftciency with T lymphocyte depleted HLA haplotype mismatched bone marrow. Proc Natl Acad Sci USA !982;79:6047-605i. 2. Ammann AJ. Hong R. Disorders of the T-cell system. In: Stiehm ER. ed. lmmunological disorders in infants and children. Philadelphia: WB Saunders Company, 1989:257-351. 3. Glanzmann E. Riniker P. Essentielle Lymphocytophthisie ein neues Krankheitsbildaus der Sauglingspathologie. Ann Paediatr 1950;175:i-32. 4. Rosen FS. Cooper MD. Wedgwood RJP. The primary immunodeficiencies (second of two parts). N Engl J Med 1984:3i i:300-3iO. 5. Touraine JL. Betuel H. Souiliet G, Jeune M. Combined immunodeftciency disease associated with absence of cell-surface HLA-A and B antigens. J Pediatr 1978;93:47-5i. 6. Hadam MR. Dopfer R, Dammer G. et al. Defective expres.sion of HLA-D region determinants in children with congenital agammaglobulinemia and malabsorption: a new syndrome. In: Albert ED, et al. eds. Histocompatibiiity testing. Berlin: Springer-Verlag, 1984:645-649. 7. Alarcon B, Regueiro JR, Amaiz-Villena A, Terhorst C. Familial defect in the surface expression of the T cell receptor CD3 complex. N Engl J Med 1988:319: 1203-1208. 8. Giblett ER, Anderson JE, Cohen F. Pollara B. Neuwissen HY. Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 1972:2:1067-1069. 9. Omenn GS. Familial reticuloendotheliosis with eosinophiiia. N Engi J Med 1984;311:300-310. 10. Barth RF. Khurana SK, Vergara GG. Lownan JT. Rapidly fatal familial histiocytosis associated with eosinophiiia and primary immunological deficiency. Lancet i972:2:503-506. 11. Ochs HD. Davis SD, Mickelson E. Lerner KJ. Wedgwood RJ. Combined immunodeftciency and reticu-
loendotheliosis with eosinophiiia. J Pediatr 1974:35: 436-465. 12. Cederbaum SD, NiwayamaG, Stiehm ER, Neerhout RC. Ammann AJ. Berman W. Combined immunodeficiency presenting as the Letterer-Siwe syndrome. J Pediatr 1974:85:466-471. 13. Leiner C. Uber erythrodermia desquamativa eine eigenanige universelle Dermatose der Brustkinder. Arch Dermatol Syphil 1908:89:163-169. 14. Scott H, Moynahan EJ. Risdon RA, Harvey BAM, Soothill JF. Familial opsonization defect associated with fatal infantile dermatitis, infections and histiocytosis. Arch Dis Child 1975:50:311-317. 15. Evans DIK, Holzed A. Macfarlane H. Yeast opsonization defect and Immunoglobulin deficiency in severe infantile dermatitis. Arch Dis Child 1977:52691-695. 16. Glover MT. Atherton DJ. Levinsky RJ. Syndrome of erythroderma. failure to thrive and diarrhea in infancy: a manifestation of immunodeftciency. Pediatrics 1988:81:66-72. 17. Gelfand EW. Olivier JM. Schuurman RK, Matheson DS. Dosch H. Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease. N Engl J Med 1979:301:1245-1249. 18. Cohen A, Mansour A. Dosch HM. Geifand EW. Association of a lymphocyte purine-enzyme deftciency (5' nucleotidase) with combined immunodeficiency. Clin Immunol Immunopathol 1980;15:245-250. 19. Akhter J. Krantman HJ. Hopper J. Rothberg RM. Lymphoproliferaiion following antigenic stimulation in severe combined immunodeficiency disease. Clin Immunol Immunopathol i98i:2O:36i-372. 20. Wyss M. Von Fliedner V, Jacot-Des-Combes E. et al. A iymphoproliferative syndrome, cutaneous dystrophy and combined immunodeficiency with lack of helper T-cell factor. Clin Immunol Immunopathol 1982:23:34-49. 21. Velders AJ. Kuis W, Van Dijk HA, et al. Omenn's syndrome: familial reticuloendotheliosis with eosinophiiia and combined immunodeficiency. Br J Dermatol l983:108:ll8-i20. 22. Karol RA. Eng J. Cooper JB. et ai. Imbalances in subsets of T lymphocytes in an Inbred pedigree with Omenn's syndrome. Clin Immunoi Immunopathol i983:27:4i2-427. 23. De Prost Y, Fischer A. Boccon-Gibod L. et al. Reticuloendotheliose D'Omenn. Ann Dermatol Venereol 1983;110:763-764. 24. Ferrando J, Ramos E, Mascaro JM, et al. Reticuloendoteiiose com eosinofilia. Doen^a de Omenn. Anais Brasileiros Dermatol 1985:60(suppl I):293-301. 25. Gelfand EW, McCurdy D. Pandu Rao C, Cohen A. Absence of lymphocyte ecto-5'-nucleotidase in infants with reticuloendotheliosis and eosinophiiia (Omenn's syndrome). Blood 1984:63:1475-1480. 26. Le Deist F, Fischer A, Durandy F, et al. Deficit immunitaire mixte et grave avec hypereosinophilie. Arch Fr Pediatr 1985:42:11-16. 27. Jouan H. Le Deist F, Nezelof C. Omenn's syndrome. Pathological arguments in favor of a graft versus host pathogenesis. Hum Pathol 1987.18:1101-1108. 28. Ruco LP, Stoppacciaro A, Pezzella F, et al. The
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Omenn's syndrome: histological, immunohistochemicai and ultrastructural evidence for a partial T cell deficiency evolving in an abnormal proliferation of T lymphocytes and S-100 -i- T6 + Langerhans-like ceils. Virchows Arch 1985.40:69-82. Friedrich W. Goldmann SF, Ebell W, et al. Severe combined immunodeficiency: treatment by bone marrow transplantation in 15 Infants using HLA haploidentical donors. Eur J Pediatr 1985;144:I25-13O. Junker AK. Ka Wah Chan, Masing BG. Clinical and immune recovery from Omenn's syndrome after bone marrow transplantation. J Pediatr 1989;H4: 569-600. Sale GE. Lerner KG, Barker EA, Schulman HM. Thomas ED. The skin biopsy in the diagnosis of acute graft-versus-host disease in man. Am J Pathol 1977:89:621-^33. Lampert IA, Janossy G, Suitters AJ, et al. Immunological anaiysis of the skin in graft versus host disease. Ciin Exp Immunoi 1982.50:123-131. Dreno B. Milpied N, Harousseau JL, et al. Cutaneous immunological studies in diagnosis of acute graft versus host disease. Br J Dermatol 1986.114:7-15. Aiba S. Tagami H. HLA-DR antigen expression on the keratinocyte surface in dermatoses characterized
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by lymphocytic exocytosis (e.g., pityriasis rosea). Br J Dermatol 1984 ;3:285-294. Bergstresser PR. Toews GB, Streilein WJ. Natural and perturbed distribution of Langerhans cells: response to ultraviolet light, heterotopic skin grafting and dinitrofluorobenzene sensitization. J Invest Dermatol 1980:75:73-77. Reinherz EL, Cooper MD, Schlossman SE, Rosen FS. Abnormaiities of T-eell maturation and regulation in human beings with immunodeficiency disorders. J Clin Invest 1981;68:699-705. Martin DW. Geifand EW. Biochemistry of diseases of immunodevelopment. Ann Rev Biochem 1981 ;50: 845-852. Quagliata F. Faig D, Conkiyn M, Silber R. Studies on the lymphocyte 5' nucieotidase in chronic lymphocytic ieukemia, infectious mononucleosis, normal subpopuiations and phytohemagglutinin-stimulated ceiis. Cancer Res 1974;39:3197-3205. Toribio ML, Hera A. Martinez AC. et ai. Activation of the interleukin-2 pathway precedes CD3-T ceil receptor expression in thymic deveiopment. Differential growth requirements of eariy mature intrathymic subpopuiations. EurJ Immunoi i989:19:9-15. Parkman R. Rappeport J. Rosen F. Human graft versus host disease. J invest Dermatot 1980:74:276-279.
Cutaneous Lesions in Severe Combined Immunodeficiency: Two Case Reports and a Review of the Literature C. Postigo Llorente, M.D., J. Ivars Amoros, M.D., F. J. Ortiz de Frutos, M.D., J. R. Regueiro, M.D., R. Llamas Martin, M.D., A. Guerra Tapia, M.D., and L. Iglesias Diez, M.D. Department of Dermatology and Immunology, Hospital 12 de Octubre, Madrid, Spain _
Abstract: Two patients with severe combined immunodeficiency (SCID) in whom cutaneous lesions were the first clinicai feature were studied. Neither the morphology nor the histology of the iesions was uniform, although we have noted some common findings that can, in subsequent cases, iead us to suspect SCID. The immunologic defects were not uniform, representing the two poles of the spectrum of SCID. We believe that early recognition of the skin lesions is very important, since the patient's life expectancy can be increased by a bone marrow transplantation (1).
Among the primary immunodeficiencies, severe combined immunodeficiency (SCID) consists of a heterogeneous group of diseases characterized by a cell-mediated and humoral deficiency (2). Two patterns of inheritance have been identified since its initial description (3), X-linked and autosomal recessive, although sporadic cases have also been reported (2). The disorder begins in the first few weeks of life, usually with clinical fmdings derived from functional alterations of T cells and with persistent oral candidiasis the most common feature. The patients are susceptible to severe viral and bacterial infections, opportunistic infections, and graft-versushost disease (GVHD) (2-4). Although cutaneous lesions in SCID are commonly described in textbooks of dermatology and pediatrics, if those resulting from infections and GVHD are excluded, reports of
Address correspondence to C. Postigo Llorente, M.D., Department of Dermatology, Hospital 12 de Oclubre, Madrid 28041, Spain.
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other skin lesions in the literature are rare. Therefore, we report two new cases of SCID with cutaneous iesions with the purpose of contributing to the disease description and clarifying their significance. CASE REPORTS Patient No. I
This giri was the fourth child of nonconsanguineous parents, born at term with a weight of 3200 g. She was healthy until age 20 days, when erythematous lesions with a slight desquamation were noted on her face, spreading to her trunk and limbs in a few days. When we saw the patient one month later, she was febrile, with rhinorrhea, irritable cough, dyspnea, anorexia, and little weight gain. Erythematous macular and papular lesions were present on the cheeks and chin, forming pink to slightly yel-
Llorente et al: Cutaneous Lesions 315
low, sharply marginaled. eczematous plaques with crust scale (Fig. 1). Isolated papuloerythematous lesions, similar to those on the face, were present on the abdomen, knees, and elbows. There was no alopecia or lesions on the mucous membranes. Family history was relevant in that a brother who had died at 2 months of age from sepsis due to coagulase-positive staphylococci had been examined at age 1 month for cutaneous lesions that, according to the parents, were similar to those of our patient. Further physical examination revealed left otitis. small occipital and inguinal adenopathy, and hepatomegaly of 2 cm without splenomegaly. Neurologic examination was normal. Laboratory test results were white blood cell count 27,000/mm\ with 839^ eosinophils (23,074/ mm-^), 10% neutrophils, 5% lymphocytes, and 2% monocytes. Red blood cell series and platelets as well as urinalysis were normal. Blood chemistry showed a slightly low protein, 4.8 g/dl. associated with an elevation of a, globulins (14.7%), and a de-
crease of 7 globulins (7.3%). Cerebrospinal fluid studies were nonnal. No thymic shadow was seen on chest roentgenogram. Gastrointestinal series and skeletal radiographs were normal. Immunologic studies showed a normal quantification of B lymphocytes, and serial determination of immunoglobulins indicated that there was a progressive decrease in IgG level (310, 240, 210 mg/dl); IgE was 15 IU/ml; IgA and IgM were absent. Isohemagglutinins were not detected and autoantibodies were negative. Complement values C3, C4, and CH50 were normal, as were serum opsonic capacity and generation of C5a. No serum inhibitors of chemotaxis were found. The numbers of T lymphocytes and subpopulations of helper and suppressor cells were normal. Proliferative response to phytohemagglutinins was within normal limits, but no response was detected in mixed lymphocyte culture. Determinations of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) were normal. The HLA typing was done in the patient's father, with a genotype of A30, A32, B18, B14, BW6, CW5. The mother's genotype was Al, A28, B8, BW6, CW7. and the child's was A32, A28, B14, BW6, sharing three paternal haplotypes and two maternal ones. Circulating maternal cells were not detected in the patient. In the first days of hospitalization, cutaneous biopsy specimens taken from abdominal and knee lesions showed a hyperkeratotic epidermis with foci of parakeratosis and moderate irregular acanthosis; there were exocytosis and spongiosis, forming intraepidermal vesicles filled with eosinophils (Fig. 2). The upper and middle dermis contained a diffuse but predominantly perivascular infiltrate of eosinophils, histiocytes, and lymphocytes (Fig. 3). Immu-
Figure 1. Pink to slightly yellow, sharply marginated, eczematous plaques with crust scale, located symmetrically on the central face.
Figure 2. Hyperkeratosis and irregular acanthosis with foci of spongiosis and an intraepidermal vesicle. (Hematoxylin & eosin; magnification 100x.)
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diac failure. She died of acute hepatic failure when she was 95 days old. at which time her white blood cell and eosinophil counts had become normal. Pathologic studies showed a hypoplastic thymus gland, with lymphoid depletion and absence of Hassal's corpuscles. The lymph nodes, spleen, and intestine contained no lymphoid follicles and plasma cells; however, some discrete eosinophilic infiltrates were seen. The changes in the skin were similar to those detected in the biopsy specimens but with less intensity. The liver had an increased volume with some necrotic areas, scarce eosinophilic infiltrates, and numerous intranuclear inclusion bodies in its hepatocytes, suggesting a hepatitis from herpes simplex virus. Patient No. 2
Figure 3. Derma! infi!trate of eosinophils, histiocytic cells, and lymphocytes. (Hematoxy!in & eosin; magnification 400 X.I
nohistochemical sludy of paraffin-em bedded sections identified the dermal histiocytic cells as typical macrophages. which expressed reactivity with MAC 387. HLA-Dr (a), and MB3; iymphoid cells were positive with T cell markers UCHLl and MTi. Furthermore, MBl was also positive and no reactivity was shown with L26. Therefore they were T lymphocytes. In the epidermis, keratinocytes were stained with MAC 387 and focally expressed HLA-DR; a decrease of intraepidermal stain with S-IOO was observed, and the same pattern as the dermal lymphocytes was demonstrated by inflammatory cells, thus confirming that they were T lymphocytes. During hospitalization the patient's skin lesions remained stable. She had various infections from which different organisms were isolated: urinary tract infection by Klehsieila, conjunctivitis by Haemophilus influenzae, acute gastroenteritis by 5a/monella enteritides, and upper respiratory infection associated with bilateral otitis by coagulase-positive Staphylococcus. Blood cultures were repeatedly negative. Later the child had progressive weight loss with worsening of her general condition and signs of car-
This girl was the second daughter of healthy nonconsanguineous parents and had no relevant family history. She was born at 36 weeks" gestation, weighing 2430 g (2nd percentile). She was breastfed until 16 days, when she developed orai candidiasis and erythematous lesions on her face and diaper area that spread to the whole body. Two days later she had a fever of 38°C. When she was hospitalized at age 21 days, a generalized maculopapular rash with desquamation was noted, being most marked on the ears, scalp, and in the nasolabial folds. Physical examination was normal and laboratory findings were as follows: white blood cell count 7270/mm^ with 64% neutrophils. 9% lymphocytes, and 14% eosinophils (1107/mm-'); platelet count was 688.000/mm^. Results of urinalysis. renal function tests. liver functions tests, and chest radiographs were normal. A smear of pharyngeal secretions, blood cultures, and cultures for enterovirus from the pharynx, urine, and stool were negative. On the second day after admission, her temperature returned to normal and the skin lesions began to fade, with desquamation. During the following two months, until her second admission, she had three outbreaks of cutaneous lesions that started as a maculopapular rash and later formed erythematous, sharply marginated, symmetrically located plaques (Fig. 4) on the trunk, faee, and extensor surface of the limbs. The lesions were eczematous. with small vesicles at their periphery. The scalp appeared to be covered by greasy scales with sparse hair (Fig. 5); the palms and soles were spared. The lesions began to desquamate on day 5 to 6, with large desquamative scales
Llorente et al: Cutaneous Lesions
Figure 4. Sharply marginated, pink, eczematous plaques on the legs.
in the nasolabial folds and retroauricular areas (Fig. 6). Histologic examination of the epidermis demonstrated foci of hyperkeratosis with parakeratosis, irregular acanthosis, and spongiosis with exocytosis of chronic inflammatory cells. Occasionally, necrotic keratinocytes and a phenomenon of satellitosis were also noted. In the papular dermis there was edema, and a diffuse though predominantly perivascular infiltrate of histiocytes, lymphocytes, and some eosinophils. Immunohistochemical studies on paraffin-embedded sections showed similar results to those of patient no. 1, except that no expression of HLA-DR was observed on the surfaces of the keratinocytes. The outbreaks of cutaneous lesions were associated with two- to three-day self-limited febrile episodes, during which time the patient continued to have oral candidiasis. When she was readmitted, she had a generalized desquamation, lesions suggestive of foUiculitis, and right external otitis. On physical examination, she had retarded growth with weight and height below
317
Figure 5. Seborrheiform, eczematous dermatitis of the scalp with crust scale. The hair appears sparse.
Figure 6. Eczematous erythroderma with large desquamative scales predominantly around the mouth.
the third percentile, and iaterocervical, occipital, and bilateral axillary adenopathy. Hepatomegaly was 4 cm and splenomegaly 3 cm. Laboratory data revealed a white blood cell count of 10,660/mm"' with 25% neutrophils, 12% lymphocytes, 12% monocytes, and 29% eosinophiJs (3029/mm^); hemoglobin 10.5 g/dl; hematocrit 34%
318 Pediatric Dermatology Vol. 8 No. 4 December 1991 with normal erythrocytic index; platelet count 390,000/mm; and hepatic enzymes of GGT, 71 IU/ L, serum glutamic oxaloacetic transaminase, 352 IU/L, and serum pyruvic oxaloacetic transaminase. 246 IU/L. Urinalysis v^as normal and there was no evidence of thymic shadow on chest radiograph. Puncture aspiration of a lymph node produced a discrete quantity of lymphoid tissue in which histiocytic cells were predominant, with scarce lymphocytes of mature aspect and few eosinophils. Immunologic studies showed hypogammaglobuJinemia and a significant decrease in the population of T3 lymphocytes with reduced proliferative response to mitogens and allogenic cells. There was only response to interleukin-2. In addition, 549f of Til lymphocytes did not express T4 and T8. determination of IgE was 76 IU/mi, and ADA and PNP were normal. An HLA typing of the patient and her parents did not show circulating maternal lymphocytes. Her father's immunologic studies were normal.
begins in the first weeks of life with eczematous lesions that usually appear first on the face and rapidly generalize. These are accompanied by lymphadenopathy, hepatomegaly and, less frequently, splenomegaly. The evolution is fatal, with diarrhea and failure to thrive. Eosinophilia and a prominent infiltration of lymph nodes by histiocytic cells are characteristic. In 1972 Barth et al (10) proposed the existence of a primary immunodeficiency in Omenn's syndrome, which later was characterized as SCID (11,12). Therefore, al! the cases described as Omenn's syndrome may have been SCID. and cutaneous lesions would be the most remarkable clinical feature. Similar disorders had been reported before 1965; that is. patients with Leiner's syndrome, which includes diarrhea, failure to thrive, and generalized seborrheic dermatitis (13). Some of these children died (14,15). and in 1988 Glover et al (16) concluded that this syndrome was highly suggestive of immunodeficiency, although not of a specific kind. One of their patients had SCID.
With the diagnosis of SCID, the patient was scheduled to undergo a bone marrow transplant, but on day 20 after admission she was transferred to an intensive care unit because of respiratory distress. Numerous consolidations were seen radiographically in both hemithoraces. The eosinophilia disappeared and she developed severe anemia; the skin showed xerosis with discrete desquamation during this time. The patient died of severe hypoxia 40 days after admission. Pneumonia from Pneumocystis carini was suspected, but autopsy was not performed.
We reviewed the literature since the first description of SCID (3), and found 32 patients with skin lesions that were due to neither infections nor GVHD (9-12.14,16-30); 21 of them were published as Omenn's syndrome. Ten chiidren had familial antecedents of a suggestive feature of SCID, but cutaneous lesions appeared in only 5 of these families (9.10.27.28). The lesions, which began between the first and twenty-first days of life, were the initial sign of the disease in all cases. In 14 patients they appeared widespread, in the form of a desquamative erythematous rash (11,12,16,17.22). Less frequently, the rash was morbilliform (18) or vesiculopapular (12). In nine patients the lesions began on the head, resembling a seborrheic dermatitis or eczema (9.20.2].23.26.28.30). and in a few the lesions began on the skin folds or in the diaper area (9.14,26). They generalized in all the children, although the involvement of palms and soles was rare (9,22). Alopecia was common, being present in 14 patients (11,12,23,24.26,29,30), and appearing either at the onset or later, progressively affecting the scaip, eyelashes, and eyebrows. Only one patient, described by Omenn (9), had lesions on the mucosa.
DISCUSSION Severe combined immunodeficiency comprises a group of congenital and usually hereditary diseases characterized by a deficiency of both T cell and B cell systems, whether or not there is lymphopenia and/or absent immunoglobulin (2). In most cases the molecular basis of the disorder is unknown. In some, however, various anomalies at the level of the lymphocyte membrane have been identified, such as the lack of expression of HLA class I and II molecules (bare lymphocyte syndrome) (5-7) and enzymatic defects (8,9). In the United States, half of the autosomal recessive cases involve a deficiency of the enzyme ADA (4). If the dermatologic manifestations secondary to infections and GVHD in patients with SCID are excluded, we find other lesions, which were first described by Omenn in 1965 (9). Omenn's syndrome
When fuily developed, the morphology of the cutaneous lesions was not uniform in all patients. In 33% the iesions evolved to an erythroderma with a progressive infiltration of the skin, especially on the face and skin folds of the limbs, having a pachydermal aspect (20,23,24,26,27). In the rest, lesions appeared as a papular rash (9,12,30) or were simply
Llorente ei al: Cutaneous Lesions 319 described as an erythematous rash. Generalized desquaniation of variable intensity was present in all children, most notably on the face and scalp, which appeared covered by thick scales and crusts (9,12,14). During the course of the disease, most children had vesicles or exudative areas, sometimes fissured, showing an eczematous aspect of the lesions, especially at the flexures of the iimbs. In our two patients, the skin lesions also appeared at the beginning of the disease, and tended to spread from the head to the rest of the body, although in patient no. 1 isolated ones were located on the limbs and abdomen. We did not observe pachyderma and infiltration at the level of skin folds, perhaps because, when described, these are late signs (23,26). The common and most striking finding in both patienis was the clinicaJ aspect of the lesions, which, although having the color and distribution of a seborrheic dermatitis, were eczematous and covered by scales and crusts, especially on the face and scalp. Therefore, we could not accept these as typical of atopic or seborrheic dermatitis. The histologic findings described in 22 patients (9-12,14.16.19-21.23,24,26-28.30) were not specific. In the dermis there was a predominantly perivascular inflammatory infiltrate of histiocytic cells, which, in some cases, had the same antigenic and enzymatic profile as Langerhans cells (28), but without Birbeck granules (20,21.24.30). In other cases, the profile was similar to macrophages (27); in addition to these cells, eosinophils in variable numbers and T lymphocytes were present. The epidermis contained foci of hyperkeratosis and exocytosis of the lymphocytes corresponding to a phenotype of suppressor T cells (27). Some patients demonstrated histologic data compatible with GVHD (27,31), but this finding was not constant (19,28). As in GVHD (32,33), there was a decrease in the number of Langerhans cells T6 (+) and an expression of HLA-DR antigens by keratinocytes (27). These facts are not specific to GVHD because some dermatoses with exocytosis of mononuclear cells may have the same characteristics (34,35). We also observed this nonspecific histology in our patients, although in patient no. 1 eosinophils were predominant in the dermal infiltrate. Immunohistochemicai studies have identified the histiocytic cells as macrophages and the intraepidermal lymphocytes as T lymphocytes. We have not found the characteristic histologic findings of GVHD, The cutaneous lesions preceded a syndrome characterized by a progressive appearance of hepa-
tomegaly in all patients, and splenomegaly and adenopathy in 26 patients (89%). All had peripheral eosinophilia with a cell count between 1898 (12) and 20,800/mm (20); IgE level was elevated in 16 patients (11,18-20,22,24-28.30). The course of the disease, with many infections, failure to thrive, diarrhea, and death, was similar to that of the classic SCID (2). In 14 patients, recurrent oral candidiasis was observed from the onset of the syndrome (9,12.14,16,18,20,22,24,28-30). Our patients' disease also began with skin lesions and progressively deveioped the rest of the ciinicai picture. Both had eosinophilia when the lesions were most evident, but the eosinophil count had become normal by the final stage of the disease; at that time patient no. 2 did not have cutaneous lesions, and in patient no. 1 the intensity of the lesions had considerably decreased. We think that the latler had a syndrome identical to that described by Omenn in 1965. In patient no. 2 we could not demonstrate the infiltration of the lymph nodes by histiocytic cells, but the clinical findings were very similar to those in Omenn's syndrome. The basis of the immunologic defect is not clear, and as in patients with classic SCID. the initial change can be seen at various stages of the lymphocytic differentiation, leading to the presence of immature lymphocytes in peripheral blood (20,22.28,36). On several occasions, a deficiency of lymphocytic 5 nucieoiidase enzyme was found (18,20.21,24-26). but it was not the rule (23,26,27). Il seems to refiect an immature state of iymphocyte differentiation or an imbalance in the proportion of lymphocyte subsets (18,25,37.38). Our two patients represent the two poles of the spectrum of SCID. In patient no. 1, the finding of Til lymphocytes that did not express T4 or T8, together with the proliferative response to interleukin-2. means that the alteration was located in immature lymphocytes (thymocytes) (39). The cutaneous lesions and other manifestations occurring in these patients have been interpreted as an abnormal immune response to an antigenic stimulus, leading to a proliferation of histiocytic cells, eosinophils, and T lymphocytes (19.25,28). Initially, the cutaneous lesions appear when there is a certain capacity for immunologic response. However, with progressive immunologic deterioration, they decrease or even disappear, as occurred in our patients. Some authors proposed the hypothesis of GVHD in relation to maternal ceils (10,11,25,27), but circulating maternal cells have never been
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found in these patients. When the histology of GVHD is seen it is possible that it has been mediated by maternal autocytotoxic celis, which are not inhibited by the suppressor T lymphocytes of the child, owing to an immunoiogic deficiency (40). We would like to emphasize the great importance of early diagnosis of SCID, since correct medical management can improve the patient's life expectancy. The dermatologist should consider this diagnosis when confronted with an infant with the types of cutaneous lesions we have described, since they can be the first clinical manifestation. Even if there are no familial antecedents of SCID, it shouid be suspected, especially when the cutaneous lesions are accompanied by eosinophiiia and oral candidiasis. REFERENCES 1. Reinherz EL, Geha R. Rappaport JM. et ai. Immune reconstitution in severe combined itnmunodeftciency with T lymphocyte depleted HLA haplotype mismatched bone marrow. Proc Natl Acad Sci USA !982;79:6047-605i. 2. Ammann AJ. Hong R. Disorders of the T-cell system. In: Stiehm ER. ed. lmmunological disorders in infants and children. Philadelphia: WB Saunders Company, 1989:257-351. 3. Glanzmann E. Riniker P. Essentielle Lymphocytophthisie ein neues Krankheitsbildaus der Sauglingspathologie. Ann Paediatr 1950;175:i-32. 4. Rosen FS. Cooper MD. Wedgwood RJP. The primary immunodeficiencies (second of two parts). N Engl J Med 1984:3i i:300-3iO. 5. Touraine JL. Betuel H. Souiliet G, Jeune M. Combined immunodeftciency disease associated with absence of cell-surface HLA-A and B antigens. J Pediatr 1978;93:47-5i. 6. Hadam MR. Dopfer R, Dammer G. et al. Defective expres.sion of HLA-D region determinants in children with congenital agammaglobulinemia and malabsorption: a new syndrome. In: Albert ED, et al. eds. Histocompatibiiity testing. Berlin: Springer-Verlag, 1984:645-649. 7. Alarcon B, Regueiro JR, Amaiz-Villena A, Terhorst C. Familial defect in the surface expression of the T cell receptor CD3 complex. N Engl J Med 1988:319: 1203-1208. 8. Giblett ER, Anderson JE, Cohen F. Pollara B. Neuwissen HY. Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 1972:2:1067-1069. 9. Omenn GS. Familial reticuloendotheliosis with eosinophiiia. N Engi J Med 1984;311:300-310. 10. Barth RF. Khurana SK, Vergara GG. Lownan JT. Rapidly fatal familial histiocytosis associated with eosinophiiia and primary immunological deficiency. Lancet i972:2:503-506. 11. Ochs HD. Davis SD, Mickelson E. Lerner KJ. Wedgwood RJ. Combined immunodeftciency and reticu-
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