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Neonatal lupus erythematosus
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Neonatal lupus erythematosus Tacie H. Draznin, M . D . , * Nancy B. Esterly, M . D . , Nancy L. Furey, M . D . , and Harvey DeBofsky, M.D.
Chicago, IL The infant of a mother with systemic lupus erythematosus (SLE) developed an extensive cutaneous eruption at 5 weeks of age. Biopsy findings were consistent with cutaneous lupus erythematosus (LE). Splenomegaly, anemia, neutropenia, and depressed total hemolytic complement levels were additional findings. The course was benign, and all manifestations disappeared by 4 months of age. Fifty-two previously reported infants with cutaneous lesions, congenital atrioventricular heart block, or hematologic manifestations of neonatal LE are reviewed. (J AM ACiD DERMATOL 1:437-442, 1979.)
Neonatal lupus erythematosus (LE) is an uncommon disorder that usually affects infants of mothers with systemic lupus erythematosus (SLE) and has only rarely been described in offspring of mothers with no evidence of connective tissue disease. The two most common clinical manifestations of neonatal L E are: (1) erythematous, scaly, atrophic cutaneous lesions that almost always resolve during infancy and (2) congenital atrioventricular block (CAVB), which can be a more serious complication. Most of the infants reported have had a single major manifestation, either cutaneous 1-14 or cardiac, '5-2a but a few infants have been noted to have both findings. 19,21,22 Hematologic abnormalities such as anemia, leukopenia, and thrombocytopenia, as well as other systemic signs, can exist concurrently but also have been observed in the absence of a rash and CAVB 24,e5 The infant described in this report had characteristic cutaneous lesions in association with hematologic and urinary abnormalities, all of which disappeared by 4 months of age. From the Departmentof Pediatrics and Dermatology,Northwestern UniversityMedicalSchool. Reprintrequeststo: Dr. NancyB. Esterly,Divisionof Dermatology, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago,IL 60614. *Present address: Departmentof Pediatrics, Universityof Virginia Medical School,Charlottesville,VA. 0190-9622/79/050437+06500.60/0 © 1979 Am Acad Dermatol
CASE REPORT
A black female infant, weighing 1,980 grams, was born on Dee. 30, 1977, at an estimated 37 weeks' gestation, to a 22-year-old woman with known systemic lupus erythematosus (SLE) of 6 years' duration. The manifestations of her SLE in the past included four of the American Rheumatology Association criteria: (1) arthritis, (2) Raynaud's phenomenon, (3) hemolytic anemia, and (4) previous acute psychosis. During pregnancy, she received prednisone, 15 mg, on alternate days. Serologic data for the mother during pregnancy were not available; but by history, pregnancy, labor, and delivery proceeded without incident. At birth, the infant was vigorous with an Apgar score of 8 at 1 minute and 9 at 5 minutes. Physical examination was unremarkable. Her nursery course was uneventful; she remained anicteric and was discharged at 5 days of age. Pertinent laboratory data obtained on the fourth day of life included a hemoglobin of 19.9 gm/dl, a hematocrit of 60%, and a white blood cell count of 6,300/mm 3 with 55% segmented forms, 2% bands, 4i% lymphocytes, and 2% monocytes, Platelets appeared adequate on smear. A chest roentgenogram was normal. She did well until 5 weeks of age, when a facial rash and scaling of the scalp were first noted. At 7 weeks of age, the eruption spread to involve the neck, trunk, and limbs; however, despite the rash, she appeared to be thriving. At 2 months of age, she was first seen in the Dermatology Clinic at Children's Memorial Hospital. She 437
438
Journal of the American Academy of Dermatology
Draznin et al
Table I. Summary of clinical and serological findings of neonates with cutaneous LE Skin lesions References
M c C u i s t i o n et al (1954, 1979) T M Epstein, Litt (1961) ~ Jackson (1964) 3 Reed et al (1967) 4 East, L u m p k i n (t969) 5 Hontani et al (1971) 6 G o l d b e r g , Diam o n d (1973) 7 W e i n e r (1973) T Soltani et al (1974) 8 V o n d e r h e i d et a! (1976) 9
L e v y et al (1976) 1° F i t z s i m m o n s et al (1977) 11 M c C u e et al (1977) TM Brustein et al (1977) TM
Sex
H &E
DIF
Anemia
F
+
F
+
-
F M F
+
+ +
F
+
+
{WBC
SPlat
RF
LE prep
ANA
m
+ + +
m
+
F Ft Ft F
+ + +
F
+
F F F F F
+ + + +
+ + -
+
+*
+ + +
+
DEJG, M -
+
DEJ Ca
-
+
-
+
m
+
m
m
m
F Mt
Ft W i n N e r et al (1977) 22 B e r u b e et al (1978) 21 Rendall, Wilkinson (1978) 13 Present case
F
+
+ +
F F F F
+
+
+
Ca
+ +
+*
+
+
*Low neutrophil count, tSiblings. CAVB: congenital atrloventricular block. DEJ: dermal-epidermal junction. DIF: direct immunofluorescence. H: hepatomegaly.
S: splenomegaly. PLAT: platelets. RF: rheumatoid factor. C: complement. G, M: immunoglobutins G and M.
had an extensive eruption on the face, lateral portion o f the chest, and distal limbs. The rash consisted of eryt h e m a t o u s , scaly, sharply d e m a r c a t e d plaques, some o f which had altered p i g m e n t a t i o n and were atrophic in a p p e a r a n c e (Fig. 1). T h e r e were m u l t i p l e small cervical and inguinal l y m p h nodes p a l p a b l e bilaterally. The heart and lungs were normal. T h e liver was palpated 1.5 c m b e l o w the right costal margin and the spleen 1.0
cm b e l o w the left costal margin. The remainder of the physical examination was unremarkable. Laboratory data were as follows: hemoglobin, 9.8 gm/dl; hematocrit, 31.6%; reticulocyte count, 2.3%; erythrocyte sedimentation rate, 38/21; white blood cell count, 6 , 6 0 0 / m m 3 with 11% segmented forms, 8% bands, 75% lymphocytes, and 6% monocytes. Platelets were 205,000/ram a. Urinalysis showed trace protein and 5 to
Volume 1 Number 5 November, 1979
Neonatal lupus erythematosus 439
Anti-
Other
Resolution
DNA
findings
skin lesions
5 mo 20 mo -
S -
5 mo 6 mo 5 mo
H,S
2too
-
1 mo
-
9 mo
-
9 mo
-
12 mo 2 mo
÷
_
m
H, S -
6rno 11 mo
-
6 mo
H,S
8too
-
4 mo
gm/dl, a hematocrit of 28%, white blood cell count of 6,900/ram 3, with 31% segmented forms, 14% bands, 2% eosinophils, 50% lymphocytes, and 3% monocytes. Platelet count was normal, and CHso was again depressed. The urine contained 0 to 6 granular casts per high-power field and no protein. ANA was absent. A skin biopsy obtained from an active lesion on the thigh demonstrated hyperkeratosis with plugging, liquefaction degeneration of the basal layer of the epidermis, incontinence of pigment, dermal edema, and a sparse dermal infiltrate of lymphocytes. Direct immunofluorescence microscopy showed deposition of C3 at the dermoepidermal junction but was negative for IgG, IgM, and IgA. By 3 months of age the rash was healing, the spleen was no longer palpable, and the infant was growing and developing normally. Except for continued anemia and a low total neutrophil count, the laboratory data were normal. At 4 months of age, no further cutaneous activity could be discerned, but striking loss of pigment was apparent in all previously involved areas. The hemoglobin and white blood cell count were rising, the platelet count and urinalysis were normal, as were Ca, C4, and CHs0 values. ANA was absent, and an antideoxyribonucleic acid (DNA) level was normal. DISCUSSION
--
+
H, S CAVB -
Not stated
H, S CAVB CAVB
Not s t a t e d Infancy
Not stated
6 mo
S
3 mo
H, S S
5 mo 5 mo
10 granular casts per high-power field. Blood urea nitrogen was 11 mg/dl, serum glutamic pyruvie transaminase, 28 U/L. Antinuclear antibody (ANA) and rheumatoid factor were absent. Quantitative immunoglobulins were normal for age. CHso was 17 mg/dl, C3 was 85 mg/dl, and C4 was 15 mg/dl. 26'm She returned to the clinic at 10 weeks of age for reevaluation. Physical examination was unchanged except for noticeable healing of the central portions of many of the cutaneous plaques (Fig. 2). Laboratory data obtained at this visit included a hemoglobin of 8.6
Since the initial report of cutaneous L E in a newborn infant b y M c C u i s t o n and Schoch, 1 twenty-two additional infants h a v e been described in the English literature 2-'4'~9,2''m (Table I). Only two infants were male (a misprint in the first case report identified the patient as a b o y ) . ' 4 Eighteen had an eruption at birth; in the remainder it was evident before 2 months o f age. In the acute stage, the rash is erythematous, scaly, and atrophic, often f o r m i n g sharply demarcated plaques within geographic configurations. Follicular plugging and telangiectasia have b e e n prominent in some infants. I n v o l v e m e n t is usually limited to the face, u p p e r portion of the chest and back, although a few infants have had a more extensive eruption. The duration o f the rash has been variable, with resolution almost always occurring by 12 months of age; minimal a t r o p h y and scarfing, as well as posfinflammatory h y p o p i g m e n t a tion, have been observed c o m m o n l y , but severe disfiguring scarfing as in discoid L E has been rare. Skin biopsies were obtained f r o m sixteen infants, and all had histopathologic findings of cutaneous LE. Direct i m m u n o f l u o r e s c e n c e mi-
440
Draznin et al
Journal of the American Academy of Dermatology
Fig. 2. Erythematous plaques with geographic borders present at 10 weeks of life.
Fig. I. Erythematous, scaly, sharply demarcated lesions on the lateral portion of the chest at 8 weeks of life. croscopy was positive in 3 out of 7 infants with deposition of C~ at the dermoepidermal junction in 2 and IgM and IgG at the junction in one. Of the twenty-four infants described in Table [, nine had hepatomegaly and/or splenomegaly, three had C A V B , and ten had hematologic abnormalities consisting of anemia, ieukopenia, and/or thrombocytopenia. The white blood cell count in some infants was normal, but the total neutrophil count was markedly depressed in five. An LE preparation was positive in 2 of 19 infants, rheumatoid factor in 1 of 9. A N A was present in 8 of 19, and anti-DNA levels were elevated in 1 of 6. Complement levels 2~t"z5 were low in 2 out of 8 infants. The short-term outcome in this group of infants was relatively good. Most o f these patients recovered during the first year of life without therapy; however, the long-term prognosis is unknown. One patient w h o recovered by the age of 5 months later developed SLE at 19 years of age, 14 and another had a positive A N A at the age of 12 years, ~,'~ M a n y o f these infants have been followed for too short a time to assess prognosis; for
others, information is not available regarding current health. in addition to the three infants with CAVB and cutaneous lesions cited in Table I, ''~'2''22 twentyseven infants born to mothers with connective tissue disorders (CTDs) have been reported with CAVB in the absence of skin lesions."~-2a In the early publications, the relationship of neonatal CAVB to maternal CTD was unrecognized. ~5''7 Twenty-five of the thirty cases have been reported during the past 2 years since this association has become better recognized. A higher percentage of males (12 of 30) was noted in the group with CAVB. Three of the thirty infants had skin lesions, ~'21'2~ and four had hepatosplenomegaly.t8'l"~'zz Few of these children were evaluated for hematologic or serologic evidence of LE, but of the four A N A titers performed, three were positive. 1'~-22 The prognosis for this group was also poorer than for the group with cutaneous lesions; 9 died in infancy or childhood,'5'~,ls-2°,22 and several others were reported to have serious cardiac disease'or congestive heart failure at the time of examination. 17,19,20 Detailed histologic studies of the hearts of infants who have died with this complication have shown extensive endocardial fibroelastosis and/or fibrosis of the conduction system. '~,'s'2° If immunomechanisms are involved, inflammatory le-
Volume 1 Number 5 November, 1979
sions and subsequent scarfing might be expected to occur in areas close to small blood vessels and in tissue with a rich vascular supply, such as is found in the conduction system. The cardiac injury in the fetus may occur early in gestation during cardiac organogenesis resulting in failure of development of the embryonic nodal anlage. If the insult occurs later, the atrioventricular node and the atrioventricular junctional tissues may be acutely inflamed and destroyed. Only two neonates with an LE syndrome have been reported 24'25 who did not have either cutaneous LE or CAVB. In one case, maternal SLE was associated with hemolytic anemia, leukopenia, and thrombocytopenia in her newborn infant3 4 The other infant had Coombs-positive hemolytic anemia, thrombocytopenia, myocarditis, pneumonitis, and a positive LE cell preparation. This infant died at 4 years of age. 2'5 Of the twenty-two mothers whose infants developed cutaneous neonatal LE, ten had definite discoid or systemic LE. Seven mothers had arthralgias and either a positive rheumatoid factor, and/or a positive ANA; three mothers felt well but had a positive rheumatoid factor. Onlytwo of the twenty-two mothers were clinically well and had no laboratory findings associated with a connective tissue disorder. It is interesting that the diagnosis of SLE was made postpartum in several mothers. One mother was well at the time of delivery but 1 year later developed symptoms, and subsequently died from complications of SLE. It is apparent that normal mothers who give birth to infants with neonatal LE should be monitored for emergence of a CTD. It is presumed that transplacental passage of maternal IgG antibody causes neonatal LE. Although ANAs have been found in babies with LE, there is no correlation between their presence and the clinical manifestations of the LE syndrome. The pathogenesis of neonatal LE is poorly understood but may be analogous to other neonatal autoimmune disorders. 28 In neonatal thyrotoxicosis, an IgG antibody, long-acting thyroid stimulator (LATS)-protector, has been identified and is thought to bind to receptor sites on the acinar cell membrane, resulting in abnormal stimulation of the thyroid gland. The manifestations disappear at
Neonatal lupus erythematosus
441
4 to 6 months of age when placentally transferred maternal IgG gradually disappears and the infant begins to synthesize its own immunoglobulin. Neonatal autoimmune disorders are transient only when the injury incurred is reversible. The skin damage in cutaneous neonatal LE is usually reversible; however, infants with cardiac involvement have permanent scarring and fibrosis. If the inflammatory process is severe, the fetus may even die in utero. The highly variable and often discordant clinical manifestations of LE in the neonate and mother are an enigma. Blocking antibodies may be present in the mother that cannot be transferred placentally. The transfer of only IgG and not antibody systems of other immunoglobulin classes may confer selective problems and/or benefits on the child. The antibody of greatest pathogenetic significance may be adsorbed by the target organ and may not be easily detected in the serum. Equally puzzling is the finding that infants of LE mothers can be clinically and serologically normal, or clinically normal but have transient serologic abnormalities such as antibody to nuclear antigens and DNA. 29-a' Genetic dissimilarities may account for differences in tissue antigen specificities and functional capacities of cooperating lymphocytic populations. Evaluation of infant-mother pairs with and without manifestations of neonatal LE may be helpful in elucidating the many factors contributing to the expression of this disorder in the newborn.
REFERENCES
1. McCuistion CH, Schoch EP Jr: Possible discoid lupus erythematosus in newborn infant, Arch Dermatol Syph 70:782-785, 1954. 2. Epstein HC, Litt JZ: Discoid lupus erythematosus in a newborn infant. N Engl J Med 265:1106-1107, 1961. 3. Jackson R: Discoid lupus in a newborn infant of a mother with lupus erythematosus.Pediatrics 33:425-430, 1964. 4. Reed WB, May SB, Tuffanelli D: Discoid lupus erythcmatosus in a newborn. Arch Dermatol 96:64-66, 1967. 5. East WR, LumpkinLR: Systemiclupus eWthematosusin the newborn. Minn Med 57:477-478, 1969. 6. Hontani N, Horino Ko Fukui J: Lupus erythematosus observed in a newborn infant. A case report and review of the literature. Acta Paediatr Jap 75:171-178, 1971. 7. GoldbergLC, DiamondA: Presumptive congenitallupus erythematosus in the newborn, Cutis 11:143-145, 1973. 8, Soltani K, Pacernick LJ, Lorinez AL: Lupus erythema-
442
9. 10,
11. 12. 13. 14. 15. 16. 17.
18. I9. 20.
Journal of the American Academy of Den'natology
D r a z n i n et al
tosus-like lesions in newborn infants, Arch Dermatol 110:435-437, 1974. Vonderheid EC, Koblenzer PJ, Ming PML, Burgoon CF Jr: Neonatal lupus erythematosus. Arch Dermatol 112: 698-705, 1976. Levy SB, Goldsmith LA, Morohashi M, Hashimoto K: Tubuloreticular inclusions in neonatal lupus erythematosus. JAMA 235:2743-2744, 1976. Fitzsimmons JS, Crawford MJ, Reeves WG: Congenital discoid lupus in the newborn. J Med Genet 14:283-286, 1977. Bmstein D, Rodriguez JM, Minkin W, Robhar NB: Familial lupus erythematosus. JAMA 238:2294-2295, 1977. Rendall JRS, Wilkinson JD: Neonatal lupus erythematosus. Clin Exp Dermatol 3:69-75, 1978. Fox RJ, McCuistion CH, Schoch EP: Systemic lupus erythematosus: Association with previous neonatal lupus erythematosus. Arch Dermatol 115:340, 1979. Plant RK, Steven RA: Complete A-V block in a fetus: A case report. Am Heart J 30:615-618, 1945. Hogg ER: Congenital acute lupus erythematosus associated with subendocardial fibroelastosis. Am J Clin Pathol 28:648~654, 1957. Wright FS, Adams P Jr, Anderson RC: Congenital atrioventricular dissociation due to complete or advanced atrioventricular heart block. Am J Dis Child 98:72-79, 1959. Hull D, Binns BAO, Joyce D: Congenital heart block and widespread fibrosis due to maternal lupus erythematosus. Arch Dis Child 41:688-690, 1966. McCue CM, Mantakas ME, Tinglestad JB, Ruddy S: Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56:82-90, 1977. Cbameides L, Tmex RC, Vetter V, Rashkind W J, Galioto FM Jr, Noonan JA: Association of maternal
21.
22. 23. 24.
25. 26. 27. 28. 29. 30. 3 I.
lupus erythematosus with congenital complete heart block. N Engl J Med 297:1204-1207, 1977. Berube S, Listep G Jr, Toews WH, Creasy RK, Heymann MA: Congenital heart block maternal systemic lupus erythematosus. Am J Obstet Gynecol 130: 595596, 1978. Winkler RB, Nora AH, Nora JJ: Familial cengenital complete heart block and maternal systemic lupus erythematosus. Circulation 56:1103-1107, 1977. Altenburger RM, Jedziniak M, Roper WL, Hernandez J: Congenital complete heart block associated with hydrops fetalis. J Pediatr 91:618-620, 1977. Siep M: Systemic lupus erythe,natosus in pregnancy with haemolytic anemia, leucopenia and thrombocytopenia in the mother and her newborn infant. Arch Dis Child 35:364-366, 1960. Nice CM Jr: Congenital disseminated lupus erythematosus. Am J Roentgenol 88:585-587, 1962. Fireman P, Zuchowski DA, Taylor PM: Development of human complement system. J lmmunol 103:25-31, 1969. Sawyer MK, Forman ML, Kuplic LS, Stiehm ER: Developmental aspects of the human complement system. Biol Neonate 19:148-162, 1971. Scott JS: Pregnancy: Nature's experimental system. Transient manifestations of immunological diseases in the child. Lancet 1:78-81, 1976. Burman D, Oliver RAM: Placental transfer of tile lupus erythematosus factor. J Clin Pathol ! 1:43-44, 1958. Beck JS, Rowell NR: Transplacental passage of antinuclear antibody. Lancet 1:134-135, 1963. Grennan DM, McCormick JN, Wajtacha CM, Carry M, Behan W: Immunological studies of the placenta in systemic lupus erythematosus. Ann Rheum Dis 37:129-134, 1978.
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Neonatal lupus erythematosus Tacie H. Draznin, M . D . , * Nancy B. Esterly, M . D . , Nancy L. Furey, M . D . , and Harvey DeBofsky, M.D.
Chicago, IL The infant of a mother with systemic lupus erythematosus (SLE) developed an extensive cutaneous eruption at 5 weeks of age. Biopsy findings were consistent with cutaneous lupus erythematosus (LE). Splenomegaly, anemia, neutropenia, and depressed total hemolytic complement levels were additional findings. The course was benign, and all manifestations disappeared by 4 months of age. Fifty-two previously reported infants with cutaneous lesions, congenital atrioventricular heart block, or hematologic manifestations of neonatal LE are reviewed. (J AM ACiD DERMATOL 1:437-442, 1979.)
Neonatal lupus erythematosus (LE) is an uncommon disorder that usually affects infants of mothers with systemic lupus erythematosus (SLE) and has only rarely been described in offspring of mothers with no evidence of connective tissue disease. The two most common clinical manifestations of neonatal L E are: (1) erythematous, scaly, atrophic cutaneous lesions that almost always resolve during infancy and (2) congenital atrioventricular block (CAVB), which can be a more serious complication. Most of the infants reported have had a single major manifestation, either cutaneous 1-14 or cardiac, '5-2a but a few infants have been noted to have both findings. 19,21,22 Hematologic abnormalities such as anemia, leukopenia, and thrombocytopenia, as well as other systemic signs, can exist concurrently but also have been observed in the absence of a rash and CAVB 24,e5 The infant described in this report had characteristic cutaneous lesions in association with hematologic and urinary abnormalities, all of which disappeared by 4 months of age. From the Departmentof Pediatrics and Dermatology,Northwestern UniversityMedicalSchool. Reprintrequeststo: Dr. NancyB. Esterly,Divisionof Dermatology, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago,IL 60614. *Present address: Departmentof Pediatrics, Universityof Virginia Medical School,Charlottesville,VA. 0190-9622/79/050437+06500.60/0 © 1979 Am Acad Dermatol
CASE REPORT
A black female infant, weighing 1,980 grams, was born on Dee. 30, 1977, at an estimated 37 weeks' gestation, to a 22-year-old woman with known systemic lupus erythematosus (SLE) of 6 years' duration. The manifestations of her SLE in the past included four of the American Rheumatology Association criteria: (1) arthritis, (2) Raynaud's phenomenon, (3) hemolytic anemia, and (4) previous acute psychosis. During pregnancy, she received prednisone, 15 mg, on alternate days. Serologic data for the mother during pregnancy were not available; but by history, pregnancy, labor, and delivery proceeded without incident. At birth, the infant was vigorous with an Apgar score of 8 at 1 minute and 9 at 5 minutes. Physical examination was unremarkable. Her nursery course was uneventful; she remained anicteric and was discharged at 5 days of age. Pertinent laboratory data obtained on the fourth day of life included a hemoglobin of 19.9 gm/dl, a hematocrit of 60%, and a white blood cell count of 6,300/mm 3 with 55% segmented forms, 2% bands, 4i% lymphocytes, and 2% monocytes, Platelets appeared adequate on smear. A chest roentgenogram was normal. She did well until 5 weeks of age, when a facial rash and scaling of the scalp were first noted. At 7 weeks of age, the eruption spread to involve the neck, trunk, and limbs; however, despite the rash, she appeared to be thriving. At 2 months of age, she was first seen in the Dermatology Clinic at Children's Memorial Hospital. She 437
438
Journal of the American Academy of Dermatology
Draznin et al
Table I. Summary of clinical and serological findings of neonates with cutaneous LE Skin lesions References
M c C u i s t i o n et al (1954, 1979) T M Epstein, Litt (1961) ~ Jackson (1964) 3 Reed et al (1967) 4 East, L u m p k i n (t969) 5 Hontani et al (1971) 6 G o l d b e r g , Diam o n d (1973) 7 W e i n e r (1973) T Soltani et al (1974) 8 V o n d e r h e i d et a! (1976) 9
L e v y et al (1976) 1° F i t z s i m m o n s et al (1977) 11 M c C u e et al (1977) TM Brustein et al (1977) TM
Sex
H &E
DIF
Anemia
F
+
F
+
-
F M F
+
+ +
F
+
+
{WBC
SPlat
RF
LE prep
ANA
m
+ + +
m
+
F Ft Ft F
+ + +
F
+
F F F F F
+ + + +
+ + -
+
+*
+ + +
+
DEJG, M -
+
DEJ Ca
-
+
-
+
m
+
m
m
m
F Mt
Ft W i n N e r et al (1977) 22 B e r u b e et al (1978) 21 Rendall, Wilkinson (1978) 13 Present case
F
+
+ +
F F F F
+
+
+
Ca
+ +
+*
+
+
*Low neutrophil count, tSiblings. CAVB: congenital atrloventricular block. DEJ: dermal-epidermal junction. DIF: direct immunofluorescence. H: hepatomegaly.
S: splenomegaly. PLAT: platelets. RF: rheumatoid factor. C: complement. G, M: immunoglobutins G and M.
had an extensive eruption on the face, lateral portion o f the chest, and distal limbs. The rash consisted of eryt h e m a t o u s , scaly, sharply d e m a r c a t e d plaques, some o f which had altered p i g m e n t a t i o n and were atrophic in a p p e a r a n c e (Fig. 1). T h e r e were m u l t i p l e small cervical and inguinal l y m p h nodes p a l p a b l e bilaterally. The heart and lungs were normal. T h e liver was palpated 1.5 c m b e l o w the right costal margin and the spleen 1.0
cm b e l o w the left costal margin. The remainder of the physical examination was unremarkable. Laboratory data were as follows: hemoglobin, 9.8 gm/dl; hematocrit, 31.6%; reticulocyte count, 2.3%; erythrocyte sedimentation rate, 38/21; white blood cell count, 6 , 6 0 0 / m m 3 with 11% segmented forms, 8% bands, 75% lymphocytes, and 6% monocytes. Platelets were 205,000/ram a. Urinalysis showed trace protein and 5 to
Volume 1 Number 5 November, 1979
Neonatal lupus erythematosus 439
Anti-
Other
Resolution
DNA
findings
skin lesions
5 mo 20 mo -
S -
5 mo 6 mo 5 mo
H,S
2too
-
1 mo
-
9 mo
-
9 mo
-
12 mo 2 mo
÷
_
m
H, S -
6rno 11 mo
-
6 mo
H,S
8too
-
4 mo
gm/dl, a hematocrit of 28%, white blood cell count of 6,900/ram 3, with 31% segmented forms, 14% bands, 2% eosinophils, 50% lymphocytes, and 3% monocytes. Platelet count was normal, and CHso was again depressed. The urine contained 0 to 6 granular casts per high-power field and no protein. ANA was absent. A skin biopsy obtained from an active lesion on the thigh demonstrated hyperkeratosis with plugging, liquefaction degeneration of the basal layer of the epidermis, incontinence of pigment, dermal edema, and a sparse dermal infiltrate of lymphocytes. Direct immunofluorescence microscopy showed deposition of C3 at the dermoepidermal junction but was negative for IgG, IgM, and IgA. By 3 months of age the rash was healing, the spleen was no longer palpable, and the infant was growing and developing normally. Except for continued anemia and a low total neutrophil count, the laboratory data were normal. At 4 months of age, no further cutaneous activity could be discerned, but striking loss of pigment was apparent in all previously involved areas. The hemoglobin and white blood cell count were rising, the platelet count and urinalysis were normal, as were Ca, C4, and CHs0 values. ANA was absent, and an antideoxyribonucleic acid (DNA) level was normal. DISCUSSION
--
+
H, S CAVB -
Not stated
H, S CAVB CAVB
Not s t a t e d Infancy
Not stated
6 mo
S
3 mo
H, S S
5 mo 5 mo
10 granular casts per high-power field. Blood urea nitrogen was 11 mg/dl, serum glutamic pyruvie transaminase, 28 U/L. Antinuclear antibody (ANA) and rheumatoid factor were absent. Quantitative immunoglobulins were normal for age. CHso was 17 mg/dl, C3 was 85 mg/dl, and C4 was 15 mg/dl. 26'm She returned to the clinic at 10 weeks of age for reevaluation. Physical examination was unchanged except for noticeable healing of the central portions of many of the cutaneous plaques (Fig. 2). Laboratory data obtained at this visit included a hemoglobin of 8.6
Since the initial report of cutaneous L E in a newborn infant b y M c C u i s t o n and Schoch, 1 twenty-two additional infants h a v e been described in the English literature 2-'4'~9,2''m (Table I). Only two infants were male (a misprint in the first case report identified the patient as a b o y ) . ' 4 Eighteen had an eruption at birth; in the remainder it was evident before 2 months o f age. In the acute stage, the rash is erythematous, scaly, and atrophic, often f o r m i n g sharply demarcated plaques within geographic configurations. Follicular plugging and telangiectasia have b e e n prominent in some infants. I n v o l v e m e n t is usually limited to the face, u p p e r portion of the chest and back, although a few infants have had a more extensive eruption. The duration o f the rash has been variable, with resolution almost always occurring by 12 months of age; minimal a t r o p h y and scarfing, as well as posfinflammatory h y p o p i g m e n t a tion, have been observed c o m m o n l y , but severe disfiguring scarfing as in discoid L E has been rare. Skin biopsies were obtained f r o m sixteen infants, and all had histopathologic findings of cutaneous LE. Direct i m m u n o f l u o r e s c e n c e mi-
440
Draznin et al
Journal of the American Academy of Dermatology
Fig. 2. Erythematous plaques with geographic borders present at 10 weeks of life.
Fig. I. Erythematous, scaly, sharply demarcated lesions on the lateral portion of the chest at 8 weeks of life. croscopy was positive in 3 out of 7 infants with deposition of C~ at the dermoepidermal junction in 2 and IgM and IgG at the junction in one. Of the twenty-four infants described in Table [, nine had hepatomegaly and/or splenomegaly, three had C A V B , and ten had hematologic abnormalities consisting of anemia, ieukopenia, and/or thrombocytopenia. The white blood cell count in some infants was normal, but the total neutrophil count was markedly depressed in five. An LE preparation was positive in 2 of 19 infants, rheumatoid factor in 1 of 9. A N A was present in 8 of 19, and anti-DNA levels were elevated in 1 of 6. Complement levels 2~t"z5 were low in 2 out of 8 infants. The short-term outcome in this group of infants was relatively good. Most o f these patients recovered during the first year of life without therapy; however, the long-term prognosis is unknown. One patient w h o recovered by the age of 5 months later developed SLE at 19 years of age, 14 and another had a positive A N A at the age of 12 years, ~,'~ M a n y o f these infants have been followed for too short a time to assess prognosis; for
others, information is not available regarding current health. in addition to the three infants with CAVB and cutaneous lesions cited in Table I, ''~'2''22 twentyseven infants born to mothers with connective tissue disorders (CTDs) have been reported with CAVB in the absence of skin lesions."~-2a In the early publications, the relationship of neonatal CAVB to maternal CTD was unrecognized. ~5''7 Twenty-five of the thirty cases have been reported during the past 2 years since this association has become better recognized. A higher percentage of males (12 of 30) was noted in the group with CAVB. Three of the thirty infants had skin lesions, ~'21'2~ and four had hepatosplenomegaly.t8'l"~'zz Few of these children were evaluated for hematologic or serologic evidence of LE, but of the four A N A titers performed, three were positive. 1'~-22 The prognosis for this group was also poorer than for the group with cutaneous lesions; 9 died in infancy or childhood,'5'~,ls-2°,22 and several others were reported to have serious cardiac disease'or congestive heart failure at the time of examination. 17,19,20 Detailed histologic studies of the hearts of infants who have died with this complication have shown extensive endocardial fibroelastosis and/or fibrosis of the conduction system. '~,'s'2° If immunomechanisms are involved, inflammatory le-
Volume 1 Number 5 November, 1979
sions and subsequent scarfing might be expected to occur in areas close to small blood vessels and in tissue with a rich vascular supply, such as is found in the conduction system. The cardiac injury in the fetus may occur early in gestation during cardiac organogenesis resulting in failure of development of the embryonic nodal anlage. If the insult occurs later, the atrioventricular node and the atrioventricular junctional tissues may be acutely inflamed and destroyed. Only two neonates with an LE syndrome have been reported 24'25 who did not have either cutaneous LE or CAVB. In one case, maternal SLE was associated with hemolytic anemia, leukopenia, and thrombocytopenia in her newborn infant3 4 The other infant had Coombs-positive hemolytic anemia, thrombocytopenia, myocarditis, pneumonitis, and a positive LE cell preparation. This infant died at 4 years of age. 2'5 Of the twenty-two mothers whose infants developed cutaneous neonatal LE, ten had definite discoid or systemic LE. Seven mothers had arthralgias and either a positive rheumatoid factor, and/or a positive ANA; three mothers felt well but had a positive rheumatoid factor. Onlytwo of the twenty-two mothers were clinically well and had no laboratory findings associated with a connective tissue disorder. It is interesting that the diagnosis of SLE was made postpartum in several mothers. One mother was well at the time of delivery but 1 year later developed symptoms, and subsequently died from complications of SLE. It is apparent that normal mothers who give birth to infants with neonatal LE should be monitored for emergence of a CTD. It is presumed that transplacental passage of maternal IgG antibody causes neonatal LE. Although ANAs have been found in babies with LE, there is no correlation between their presence and the clinical manifestations of the LE syndrome. The pathogenesis of neonatal LE is poorly understood but may be analogous to other neonatal autoimmune disorders. 28 In neonatal thyrotoxicosis, an IgG antibody, long-acting thyroid stimulator (LATS)-protector, has been identified and is thought to bind to receptor sites on the acinar cell membrane, resulting in abnormal stimulation of the thyroid gland. The manifestations disappear at
Neonatal lupus erythematosus
441
4 to 6 months of age when placentally transferred maternal IgG gradually disappears and the infant begins to synthesize its own immunoglobulin. Neonatal autoimmune disorders are transient only when the injury incurred is reversible. The skin damage in cutaneous neonatal LE is usually reversible; however, infants with cardiac involvement have permanent scarring and fibrosis. If the inflammatory process is severe, the fetus may even die in utero. The highly variable and often discordant clinical manifestations of LE in the neonate and mother are an enigma. Blocking antibodies may be present in the mother that cannot be transferred placentally. The transfer of only IgG and not antibody systems of other immunoglobulin classes may confer selective problems and/or benefits on the child. The antibody of greatest pathogenetic significance may be adsorbed by the target organ and may not be easily detected in the serum. Equally puzzling is the finding that infants of LE mothers can be clinically and serologically normal, or clinically normal but have transient serologic abnormalities such as antibody to nuclear antigens and DNA. 29-a' Genetic dissimilarities may account for differences in tissue antigen specificities and functional capacities of cooperating lymphocytic populations. Evaluation of infant-mother pairs with and without manifestations of neonatal LE may be helpful in elucidating the many factors contributing to the expression of this disorder in the newborn.
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Journal of the American Academy of Den'natology
D r a z n i n et al
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