210

BRIEF REPORT

NEONATAL LUPUS ERYTHEMATOSUS WITH HEART BLOCK:

ANTIBODIES FAMILY STUDY OF A PATIENT WITH ANTI-SS-A AND SS-B

MICHAEL D. LOCKSHIN, ALLAN GIBOFSKY, CAROL L. PEEBLES, IRMA GIGLI, MARILENA FOTINO, and SIDNEY HURWITZ

Neonatal lupus erythematosus, a syndrome consisting of lupus-like rash and lupus-associated he- matologic and serologic abnormalities, is a rare, tran- sient phenomenon found in children of mothers with idiopathic systemic lupus erythematosus (SLE) or undefined connective tissue disease and, occasionally, no recognized rheumatic disease (1,2). Congenital atrioventricular heart block, also rare, is frequently associated with a maternal SLE-like illness that is either present or nascent (3-6). At least 9 children with congenital heart block and/or neonatal lupus have had transient antibody to the nuclear antigen SS-A (Ro) or SS-B (La) (7-9).

Although an increased frequency of the histo- compatability antigens HLA-DR2 and DR3 has been

From the Hospital for Special Surgery, afliliated with the Cornell University Medical College, New York, NY; University of Colorado Health Sciences Center, Denver, CO; New York Blood Center, New York, NY; New York University School of Medicine, New York, NY; Yale University School of Medicine, New Haven, CT.

Michael D. Lockshin, MD: Professor of Medicine, The Hospital for Special Surgery affiliated with Cornell University Medical College; Allan Gibofsky, MD: Assistant Professor of Medi- cine, The Hospital for Special Surgery affiliated with Cornell University Medical College; Carol L. Peebles, MS,MT: Research Assistant, Division of Rheumatic Disease, University of Colorado Health Sciences Center; Irma Gigli, MD: Professor of Dermatology and Experimental Medicine, University of California at $an Diego; Marilena Fotino, MD: Director, Tissue Typing Laboratory, New York Blood Center and Assistant Professor of Clinical Biochernis- try, Cornell University Medical College; Sidney Hurwitz, MD: Associate Clinical Professor of Pediatrics and Dermatology, Yale University School of Medicine.

Address reprint requests to Michael D. Lockshin, MD, The Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Submitted for publication June 28, 1982; accepted in re- vised form August 13, 1982.

reported in patients with SLE (lO,ll), and an unusual frequency of HLA-BS, DR3 may occur in mothers of children with congenital heart block (12), family stud- ies of congenital heart block and neonatal lupus with HLA typing have not yet been reported.

We have recently seen a child with both neona- tal lupus and congenital heart block who shared anti- body to SS-A and SS-B with her mother, yet did not inherit the chromosome containing HLA-DR3. Find- ings in this family have implications for our under- standing of the pathogenesis of SLE and neonatal lupus.

CASE REPORT

Proposita (case IIIb). A female child of white parents first came to medical attention in her seventh in utero month because of bradycardia. Congenital heart block was diagnosed. The pregnancy was other- wise uneventful, and she was born at term on Febru- ary 14, 1981. Heart block was confirmed, but no other cardiac or congenital abnormalities were present. Ane- mia, thought to be due to iron deficiency, character- ized her early extrauterine life. At 3% months of age butterfly erythema appeared together with a hypopig- mented atrophic plaque with telangiectasia. The rash subsided without treatment by 5 months of age. Al- though she has had two episodes of high fever, her growth and development have been normal through her first year. Repeat urinalyses have been normal.

Case IIc. The mother of the proposita is a 24- year-old gravida 3 para 2 woman with no prior serious medical illness. She has had photosensitivity (rash) and episodes of mild alopecia. History and physical examination in July 1981 demonstrated no clinical

Arthritis and Rheumatism, Vol. 26, No. 2 (February 1983)

BRIEF REPORTS

I . An2488Cn7DR3 A3B7Cn7DR6 ____ AlWCn7DR3

AlBBCw7DR3

21 1

AZBn60Cw3DR6 An33EnJ5Cn-DR4 __-

evidence of SLE or Sjogren’s syndrome. In July 1982 she developed lymphadenopathy and xerophthalmia. Although her serologic abnormalities had improved, her Westergren erythrocyte sedimentation rate was 46 mm/hour and her white blood cell count 3,600 per mm’. Her 4-year-old son (case IIIc) is normal.

MATERIALS AND METHObS

Family. Seven of the 8 available family mem- bers were interviewed and blood samples obtained in July 1981 or January 1982. Family member IIa refused; Ib, who died of cirrhosis, had HLA types inferred. Signs and symptoms of connective tissue disease were sought.

Antinuclear antibodies (ANA). Fluorescent ANA screening at The Hospital for Special Surgery and at the University of Colorado used 1:lO serum dilution and mouse kidney substrate. ANA profiles performed at the University of Colorado sought anti- body to RNP and Sm antigens by double immunodiffu- sion against an extract of rabbit thymus, and antibody to SS-A, SS-B, and RAP by double immunodiffusion against a cell-free extract of Wil-2 human B lympho- cytes (13). Antibody against double-stranded DNA was assayed by the Farr technique (14).

Complement. Hemolytic complement was de- termined at The Hospital for Special Surgery by the method of Kent and Fife (15). Complement compo- nents were determined at New York University ac- cording to previously published methods (16).

HLA typing. Histocompatibility phenotyping for serologically detectable antigens of the HLA-A, B, C, and DR series was performed in accord with standard methods, previously described (17).

RESULTS

Figure I illustrates the family pedigree. There is no consanguinity. Table 1 lists the relevant serologic and genetic findings. Important results are: 1) the proposita did not inherit the maternal haplotype con- taining HLA-DR3; 2) at the time of first examination both cases IIc and IIIb had antibody to both SS-A and SS-B; however, at second examination 6 months later IIIb had returned to serologic normality; 3) at first examination both IIc and IIIb were hypocomplemen- temic, but IIIb has subsequently become normal. Case IIc, although now serologically normal, may have developed Sjogren’s syndrome 17 months after deliv- ery of her child; 4) Ia had borderline low C4 and IIIa

I l l . AlBw51CwlDR2 AlBw51CnlDR2 ___ AnZ4BBCn7DR3 A2BnWCn3DR6

Figure 1. Pedigree of the family with HLA types. Solid circle with arrow = proposita (clinical and serologic abnormalities); half closed circle = serologic abnormalities. In each row members are labeled A, B, C, D left to right. Cases Ib and IIa were not examined. HLA type is presumed for case Ib.

borderline low CHSO, but other complement assays were normal.

DISCUSSION

The proposita is the tenth reported patient combining neonatal lupus and antibody to SS-A or SS- B and the fourth with both neonatal lupus and congeni- tal heart block who has these antibodies (7-9). Al- though we cannot date the acquisition of antibody in the mother nor determine the source (mother or child) or the type of antibody in the child, the likelihood is that maternal antibody was present during gestation, and that the child’s antibody is in fact passively transferred maternal antibody (18). The close associa- tion of neonatal lupus and congenital heart block with antibodies to SS-A (10 of 10 studied infants) suggests a pathogenetic relationship. The finding of transient hypocomplementemia in the currently reported child-and the occurrence in other neonatal lupus children of hepatosplenomegaly and, rarely, glomeru- lonephritis (2 l j sugges t s that the immunologic events occurring in the child with neonatal lupus are quantita- tively important. In the present family the initial complement profiles suggested the possibility of con- current C4 deficiency, but detailed repeat study failed to confirm the abnormality. C4 deficient SLE patients also have antibody to SS-A (‘IT Provost, personal communication).

The finding of discordance for the haplotype containing BH,DR3 between the proposita and her mother suggests that while genetic factors are impor- tant, histocompatibility genes of the HLA system may

212 BRIEF REPORTS

Table 1. Serologic and clinical data of family members

Antibodv tested'

anti- Case no. , anti- anti- anti- anti- anti- DNA Complement t

relations hip Agelsex ANA SS-A SS-B Sm RNP RAP % CHSO C4 C3 Clinical

la 46/M I +sp ? <l:4 - - 1.4 12 190 Low Normal Normal Grandfather's

brother

Grandmother

Uncle

Ic S8/F 0 0 0 0 0

IIb 291.M 0 0 0 - -

Ilc (July81) 25/F 3+sp + + 0 0

Mother (Jan 82) 3+sp >1:256 >1:256 - - Ild 24/M 0 0 0 0 0

Father llla 41M 0 0 0 0 0

normal

0 3 232 Normal Normal Normal

1:4 0 190 Normal - Normal

- 9 119 Low Low Normal

- 10 <50 Low Low Normal 0 2 211 Normal Normal Normal

<1:4 0 129 Normal Normal Normal

normal

Brother

Proposita (Jan 82) 0 0 0 0 0 0 1 187 Normal Korrnal No rash

* Antinuclear antibodies (ANA) were tested at I : 10 dilution and graded 0-4+. sp = speckled pattern of immunofluorescence. Anti-DNA . .

l l lb (July 81) I/F 2 t sp + + 0 0 - 8 122 Low Low Rash

antibody was tested by the Farr technique. normal <20% binding equivocal result. t CHSO normal = >IS0 units/ml. For other antibodies see text.

not be the sole factors determining disease susceptibil- ity. In all likelihood, genes of the HLA system are not closely linked to those actually responsible for the disease since neonatal lupus is very rare while the B8,DR3 haplotype is not, and the present patient with neonatal lupus does not have the B8,DR3 haplotype. The possibility that the proposita may represent an HLA disease gene recombinant cannot be excluded in this study. On the other hand, the proposita types for HLA-DR2. which is the other histocompatibility de- terminant associated with SLE ( I I ) , but her 4-year-old brother is healthy and types for both DR2 and DR3. The proposita's sex may be important since serologic abnormalities were unequivocally present only in fe- males and not in DR3 males in this family.

Several other observations about neonatal lu- pus are intriguing. First, although interpretations are at this time speculative, the majority of reported infants (34 of 38) with neonatal lupus are female ( I ,2,6-9,19-22). Whether this reflects a selective male fetal loss or a predisposition of female infants to develop neonatal lupus is unknown; sex distribution of normal children of mothers with SLE appears normal (unpublished observation). Neonatal girls differ hor- monally from boys (23): testosterone may therefore suppress illness in males or estrogen may permit expression in females (24). Alternatively, a non-hor- monal attribute of femaleness might determine suscep- tibility to neonatal lupus (and perhaps SLE).

+ = positive. titer not ascertained; 0 = negative; - = not tested; ? =

Second, the mothers of congenital heart block and neonatal lupus babies tend to havc subclinical or atypical rather than typical SLE. The prevalence of speckled ANA and/or antibody to SS-A and SS-B rather than to double-stranded DNA or Sm supports this observation, although Sjogren's syndrome has not been characteristic of the mothers. Similarly. as judged by the case reports, neonatal lupus patients have less nephritis, arthritis, fever, and cytopenias than do children with spontaneous SLE. Neonatal lupus and the disease of mothers of children with neonatal lupus or congenital heart block may therefore not be good models for spontaneous SLE.

Third, 2 children reported (in 1954 and 1964) to have neonatal lupus have at ages 13 and I9 developed clinically typical SLE (19.20). Whether the redevelop- ment (or new development) of disease in these patients is a function of immunologic or hormonal changes of adolescence, reexposure to an environmental agent. or some other factor is unknown in these patients. Fur- ther studies on our proposita as well as that of her B8,DR3 sibling when they reach adolescence and adulthood may help unravel this puzzle.

ACKNOWLEDGMENTS Drs. Maurice Druzin. Wah Ngo Lirn, and Aaron

Levin brought this family to our attention. Dr. Jane Schaller offered advice. Mrs. Hjordis Kerezman expertly typed the manuscript.

BRIEF REPORTS 213

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