A 10-year retrospective study of neonatal lupus erythematous in China.

BACKGROUND: Neonatal lupus erythematosus (NLE) is not a common disease. The death rate of complete congenital heart block (CCHB), which is the most severe clinical manifestation, is as high as 20% to 30%, so early recognition of infants at risk is important. OBJECTIVES: To investigate the clinical features and long-term prognosis of NLE. METHODS: Twenty-five cases with NLE were reviewed. The clinical manifestations of patients and their mothers were summarized and analyzed. Autoantibodies were detected, and long-term follow-up was carried out. RESULTS: There were 25 patients (male:female ratio of 11:14). CCHB was detected in only 3 of the 25 patients (12%). Cutaneous neonatal lupus erythematosus (CNLE) was seen in 22 of the 25 patients (88%). Eight babies were treated with intravenous immunoglobulin (IVIG), five of whom had a prolonged PR interval that reverted to normal sinus rhythm. During the follow-up of the patients, we found only two patients with CCHB without a pacemaker, who both exhibited growth delay. One patient with CCHB without a pacemaker died. CONCLUSIONS: Children with NLE have an excellent outcome when only skin lesions are present. Even the hepatic, hematological and neurological abnormalities are transient, with generally good outcomes. IVIG might have some effectiveness due to enhanced anti-inflammatory activity to treat early diseases that may be reversible (e.g. prolonged PR interval). The long-term prognosis for patients with NLE is still under investigation, and some infants with NLE may progress to other autoimmune diseases later in childhood.

52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart.

The 52-kD SS-A/Ro protein is one of the antigenic targets strongly associated with the autoimmune response in mothers whose children have manifestations of neonatal lupus. In addition to the cDNA clone we previously reported for the full-length 52-kD SS-A/Ro protein, an interesting MOLT-4 cDNA clone, p52-2, was found to have an internal deletion of 231 nucleotides including the domain encoding the leucine zipper motif. To further investigate the nature of this deletion, genomic DNA clones were isolated from a lambda FIXII library. The complete gene for the full-length 52-kD protein (alpha form, 52 alpha) spans 10 kb of DNA and is composed of seven exons. Exon 1 contains only the 5' untranslated sequence, while the translation initiation codon is located 3 kb downstream in exon 2, which also encodes the three zinc finger motifs. Exon 4 encodes amino acids 168-245, including the coiled coil/leucine zipper domain. Exon 7 is the longest and encodes the rfp-like domain and the 3' untranslated region. The cDNA p52-2 can now be accounted for as a product of alternative messenger RNA (mRNA) derived from the splicing of exon 3 to exon 5, skipping exon 4, which results in a smaller protein (52 beta) with a predicted molecular weight of 45,000. An initial approach to identifying this alternatively spliced form in the human heart used a ribonuclease protection assay. Using an RNA probe corresponding to bases 674-964 of the full-length cDNA, two protected mRNA fragments were identified, a 290-bp fragment corresponding to expression of 52 alpha and a smaller fragment of 144 bp, the predicted size of 52 beta. Using reverse transcription followed by polymerase chain reaction, cDNAs from a 16-wk fetal heart, 24-wk heart, and adult heart were amplified with primers flanking exon 4. Two polymerase chain reaction products were observed in each tissue, one 1.0 kb likely representing 52 alpha and a second 0.78 kb, consistent with 52 beta. The 0.78-kb fragment identified in the 16-wk heart was cloned, and DNA sequencing confirmed the 52 beta type. Immunoprecipitation of in vitro-translated 35S-labeled 52 beta form was performed to evaluate the antigenicity of this novel form of 52-kD SS-A/Ro. 26 (87%) of 30 sera tested from mothers whose children were known to have neonatal lupus immunoprecipitated the 52 beta form.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-cardiac manifestations of neonatal lupus erythematosus.

Neonatal lupus erythematosus (NLE) is characterized by the transplacental passage of maternal anti-Ro and/or anti-La antibodies and characteristic illnesses in the foetus/neonate. Most attention has focused on the most serious complication- cardiac involvement. This article will focus on non-cardiac involvement. Skin involvement (cutaneous NLE) is present in 15-25% of children with NLE. The rash of NLE tends to be photosensitive but may be present at birth or in non-sun exposed areas. It is most frequently seen around the eyes, not in the malar area, but also occurs in other parts of the body. The pathology resembles the rash of subacute cutaneous lupus erythematosus. Anti-Ro antibodies are present in >95% with the remaining mothers having anti-U1RNP antibodies only. Asymptomatic elevation of liver function tests, which may be associated with evidence of cholestasis, is seen in 10-25% of cases of NLE. Mild hepatomegaly and less commonly splenomegaly may be present. Liver involvement seen in isolation or associated with other features. The pathology resembles idiopathic neonatal giant cell hepatitis. Any haematological lineage, neutropenia and thrombocytopenia most commonly, may be affected by NLE. Haematological involvement is almost always asymptomatic. There are protean manifestations of neurologic involvement in NLE: hydrocephalus, non-specific white matter changes, calcification of the basal ganglia and a 'vasculopathy'. The most unusual feature of NLE is the radiographic finding of stippling of the epiphyses (chondrodysplasia punctata). Overall, non-cardiac involvement of NLE is more common than cardiac. The study of these manifestations may lead to new insight into how autoantibodies lead to disease.

Congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

Neonatal lupus erythematosus is an uncommon disease caused by transplacental passage of maternal anti-Ro (SS-A), anti-LA (SS-B), or anti-U1RNP antibodies. Cutaneous findings of neonatal lupus are variable, but annular, erythematous plaques occurring within a few weeks of birth are most typical. Cutaneous lesions of congenital onset lupus erythematosus can differ from that of neonatal lupus erythematosus, presenting with atrophy or scarring, and less commonly, erosions. We report an unusual case of congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

[An infant with facial skin lesions]. / Een zuigeling met huidafwijkingen in het gelaat.

A 42 year old woman was diagnosed with SLE, ANA and anti-SSA antibodies were positive. Her daughter had cutaneous lesions typical of neonatal lupus erythematosus. Children with NLE can also develop cardiac conducting disturbances. These are associated with significant morbidity and mortality, therefore, monitoring is required in patients with anti-SSA antibodies.

Neonatal lupus erythematosus.

Neonatal lupus erythematosus (NLE) is a rare syndrome of newborns and infants defined by the presence of maternal autoantibodies and the characteristic clinical features of the infant. The clinical findings most often reported are congenital heart block and cutaneous lesions; however, many children have cardiomyopathy, hepatobiliary disease, and/or hematologic diatheses. We present the case of a 1-day-old African American boy who presented with an annular, ulcerated facial eruption at birth and went on to develop subacute cutaneous LE (SCLE) and heart block.

Neonatal lupus erythematosus: a cutaneous cases based update.

BACKGROUND: Neonatal Lupus Erythematosus (NLE) is an uncommon autoimmune disease characterized by cutaneous, hepatic, hematological, neurological and cardiac involvement. CASE PRESENTATION: Here we report four cases of cutaneous NLE which were referred to our department in the last 10 years and update literature. The newborns presented with different skin, clinical and laboratory features. This underlines the phenotypic variability of NLE. We investigated the passage of maternal antinuclear antibodies (ANA) and extractable nuclear antigen antibodies (ENA) - particularly anti-Ro/SSA, anti-La/SSB and anti-U1 ribonucleoprotein RNP - through the placenta. Despite the positive family background, cutaneous NLE and serological data improved in infants within 4 months without treatment. CONCLUSION: The evolution of cutaneous NLE may be the spontaneous regression of lesions within six months without progression to Systemic Lupus Erytehmatosus.

Transient autoimmunity related to maternal autoantibodies: neonatal lupus.

Neonatal lupus (NLE) is an autoimmune disease associated with maternal antibodies to Ro/La and characterized by cutaneous lesions, heart block, cardiomyopathy, hepatobiliary disease, and hematologic cytopenias. In most cases, only one organ is affected, although multiple organ involvement is not unusual. Since NLE is presumably caused by maternal autoantibodies, the disease process is transient. However, cardiac NLE, in particular, may be fatal or persistently disabling. Optimal therapy has not yet been determined. Mothers of babies with NLE are often initially asymptomatic, but eventually most develop symptoms of autoimmune disease, particularly diseases associated with anti-Ro/La autoantibodies, such as Sjogren's syndrome and systemic lupus erythematosus. Children who have had NLE are probably at increased risk for autoimmunity later in life, sometimes as early as pre-adolescence, but the magnitude of the risk for the children is not known. Only a small percentage of babies exposed to maternal autoantibodies to Ro and/or La develop NLE. The factors governing which babies develop disease and, if disease develops, which organs will be affected have yet to be fully elucidated. In this review the clinical features, diagnosis, therapy, and prognosis of NLE are discussed, and a summary of experimental data relating to pathogenesis is presented.

Neonatal lupus erythematosus: a review of the racial differences and similarities in clinical, serological and immunogenetic features of Japanese versus Caucasian patients.

There has been tremendous interest in neonatal lupus erythematosus (NLE) since the reports of anti-Ro/SSA antibodies as a diagnostic marker. Recent studies, including ours, have revealed racial differences as well as similarities in the clinical features and immunogenetic backgrounds of Japanese and Caucasian patients with NLE. The frequency of photosensitivity and subacute cutaneous LE lesions is not high in Japanese infants with NLE, which is in sharp contrast to their Caucasian American counterparts. The majority of Japanese infants with NLE develop annular, erythematous or edematous lesions which have also been reported in association with Sjögren's syndrome. The frequency of isolated congenital heart block (CHB) is about 50% in Japanese anti-Ro/SSA positive neonatal lupus infants; this is similar to the frequency among Caucasians. The HLA-DR3 phenotype, which is found in the great majority of Caucasian mothers of NLE infants, is absent in Japanese mothers. Finally, both Japanese and Caucasian children with CHB are often identical to their mothers in their alleles of HLA-DRB1, DQA1 and DQB1 loci.

Focal seizures as an unusual presentation of neonatal lupus erythematosus.

Neonatal lupus erythematosus is an uncommon passive autoimmune disease in which there is a transplacental passage of anti-Ro/SSA and/or anti-La/SSB maternal autoantibodies. Common clinical manifestations include cardiac disease, notably congenital heart block, cutaneous lupus lesions, hematologic disorders, and hepatobiliary disease. During the past decade, however, it has become clear that central nervous disease may also be a manifestation of neonatal lupus. We report a male neonate with the disease who had focal seizures in addition to cutaneous lupus, anemia, and thrombocytopenia. Brain ultrasound revealed normal ventricular size without a midline shift or intracranial or intraventricular hemorrhage. A brain CT showed generalized low density involving the periventricular and deep white matter. A sleep EEG revealed rare spikes axial to the right parietal lobe. The neonate had a high titer of antinuclear antibodies (1:640) with a speckled pattern, anti-Ro/SSA and anti-La/SSB antibodies, but no anti-dsDNA antibodies. He was given anti-convulsant drugs with dramatic improvement of his symptoms. One month later, a sleep EEG was normal, and he had no further seizures.

Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

The health of mothers of children with cutaneous neonatal lupus erythematosus differs from that of mothers of children with congenital heart block.

PURPOSE: Neonatal lupus erythematosus is caused by the transplacental passage of maternal autoantibodies. The aim of this study was to determine the risk of connective tissue disorders in mothers of children with cutaneous neonatal lupus erythematosus, as compared with the risk in mothers of children with congenital heart block, which is also often caused by maternal autoantibodies. SUBJECTS AND METHODS: We prospectively studied all mothers of children with cutaneous neonatal lupus erythematosus during a 14-year period at the Hospital for Sick Children, Toronto, Ontario, Canada. We identified 28 mothers, of whom 24 were eligible for study. The health and antibody status of the mothers were determined at the birth of the child and at followup. RESULTS: All mothers had anti-Ro antibodies at the time of birth. Initially 10 mothers were healthy and 14 mothers had either a defined (n = 9) or an undifferentiated (n = 5) autoimmune disorder. At a mean follow-up of 7 years, 13 (1 of whom had died) had a defined connective tissue disease, and 5 had an undifferentiated autoimmune disorder. Only 6 (25%) remained asymptomatic. By comparison, 36 (56%) of 64 mothers of children with congenital heart block were asymptomatic at follow-up (P <0.005). CONCLUSIONS: The majority of mothers of children with cutaneous neonatal lupus erythematosus had a defined or undifferentiated autoimmune disorder at the time of the child's birth, and others developed these conditions during follow-up. The health of these mothers appears to differ from that of mothers of children with congenital heart block.

Thrombocytopenia in the neonatal lupus syndrome.

Thrombocytopenia has been documented infrequently in association with congenital heart block or lupus dermatitis in the neonatal lupus erythematosus syndrome. We report the cases of two infants with transient neonatal thrombocytopenia born to mothers with connective-tissue disease. Both mother/infant pairs were Ro(SS-A) antibody positive. Although the finding of neonatal thrombocytopenia in the presence of maternal connective-tissue disease suggests an autoimmune thrombocytopenia, platelet antibody studies were negative in both mother/infant pairs. We have found the Ro (SS-A) antibody with increased frequency in idiopathic thrombocytopenic purpura and thrombocytopenia associated with Sjögren's syndrome, but the nature of the association is unknown. We suggest that thrombocytopenia in our patients is a manifestation of the neonatal lupus erythematosus syndrome. This syndrome should be included in the differential diagnosis of neonatal thrombocytopenia.

Neonatal lupus: clinical features and management.

Neonatal lupus is an uncommon autoimmune disease manifested primarily by cutaneous lupus lesions and/or congenital heart block. Maternal autoantibodies of the Ro/La family are present in virtually every case, although only approximately 1% of women who have these autoantibodies will have a baby with neonatal lupus. The cutaneous lesions of neonatal lupus may be present at birth, but more often develop within the first few weeks of life. Lesions are most common on the face and scalp, often in a distinctive periorbital distribution. Lesions tend to resolve in a few weeks or months without scarring. The most common cardiac manifestation of neonatal lupus is complete heart block. Heart block typically begins in utero during the second or third trimester. In some cases, heart block begins as first- or second-degree block and then progresses to third-degree block. Complete heart block, once established, appears to be irreversible. In some cases, cardiomyopathy occurs together with complete heart block. Most cases have been noted at birth, but delayed dilated cardiomyopathy has been reported. There have been a few cases of endocardial fibroelastosis occurring in the absence of congenital heart block. Hepatobiliary disease occurs in about 10% of cases. Three types of hepatobiliary disease have been observed: liver failure occurring at birth or in utero, transient conjugated hyperbilirubinemia occurring in infants, or transient transaminase elevations occurring in infants. Hematologic disease, consisting of thrombocytopenia, neutropenia, or anemia, occurs in about 10% of cases. It is common for children with neonatal lupus not to have the full expression of disease, but rather to have only one or two organ systems involved. The diagnosis rests largely on the finding of compatible clinical manifestations plus maternal autoantibodies to Ro and/or La, or, in a few cases, to U1 ribonuclear protein. Although the pathogenesis has not been conclusively established, accumulating evidence, including evidence from animal models, implicates autoantibodies in the pathogenesis of the disease. Therapeutic interventions include attempts at prevention, early intervention, and treatment of well established disease, mainly through the use of systemic corticosteroids. Optimal therapy has yet to be determined. The long-term prognosis for children who have had neonatal lupus is still under investigation, but some children who had neonatal lupus have developed other autoimmune diseases later in childhood. About half of the mothers are asymptomatic at the time of presentation of the child, but some of these women eventually develop symptoms of autoimmune disease.

Clinical characteristics of neonatal lupus erythematosus.

Neonatal lupus erythematosus is a rare disorder caused by transplacental autoantibodies from the mother to the fetus. This syndrome is characterized by congenital heart block and/or cutaneous lesion. A total of 10 cases of neonatal lupus erythematosus were diagnosed at the National Taiwan University Hospital from 1988 through 1998. The incidence of cardiac anomaly and other clinical features in patients with neonatal lupus erythemayosus in this study was compared with those in previous studies. Results showed that 50% of patients had congenital heart block and/or cutaneous lesion, which is compatible to previous statistics. However, the findings showed that 80% of the patients were female and 90% of the mothers had acquired an autoimmune disorder, which were much higher compared with that of other studies. To date, no definite treatment is suggested prenatally to prevent the occurrence of congenital heart block, but careful maternal screening and serial fetal echocardiogram are warranted.

[Neonatal cutaneous lupus. Necessary interdisciplinary collaboration]. / Lupus cutané néonatal. Nécessaire collaboration interdisciplinaire.

INTRODUCTION: Neonatal lupus erythematosus is a rare syndrome (affecting 5% of the children born of mothers with lupus), characterized essentially by cutaneous lesions and/or congenital auricular-ventricular heart block. It is due to the transplacental passage of maternal antibodies (anti-SSA or anti-SSB, or occasionally anti-U1RNP antibodies) into the fetal circulation. OBSERVATION: We report a case of neonatal lupus erythematosus, having appeared 4 weeks after birth. The 26 years old mother exhibited systemic lupus erythematosus concomitant to Gougerot-Sjögren's syndrome, with positive antinuclear factors (1/2560), native anti-DNA, anti-SSA and anti-SSB antibodies and anticardiolipin antibodies. During pregnancy, the mother had been treated with aspirin at the dose of 100 mg/day, followed by subcutaneous enoxaparin 0.4 ml/day, and combined with prednisone 10 mg/d and hydroxychloroquine 400 mg/day. Early and regular cardiac monitoring of the foetus was performed. The clinical examination and the electrocardiogram at birth were normal. Four weeks later, the infant presented with erythematous cutaneous lesions with atrophic center. No systemic treatment was initiated and the lesions partially regressed. CONCLUSION: Cutaneous lesions can also appear after the 4th week of life. It is important that the pediatricians clinically monitor all the children born to mothers exhibiting anti-SSA or anti-SSB antibodies, at least during the first 7 months of life.

[Neonatal lupus erythematosis and atrial-ventricular block. A case report and review of the literature]. / Lupus erythemateux neonatal et bloc auriculo-ventriculaire. A propos d'un cas avec revue de la littérature.

Neonatal lupus erythematosus is a rare syndrome. It is characterized by a transient lupus dermatitis and congenital heart block. The immunopathogenesis of the disease has been linked to the presence of the SSA antibody. In this report, we describe a symptomatic congenital heart block in a 13-year-old male whose mother had documented systemic lupus erythematosus. We also discuss how to manage a woman with lupus erythematosus and positive antiSSA/Ro antibodies. We conclude that patients with neonatal lupus and their mothers should be observed closely before delivery and for prolonged periods for signs of active disease.

Lesiones cutáneas diagnósticas de enfermedad sistémica transitoria / Diagnostic skin lesions of transient systemic disease

El lupus neonatal cutáneo es una entidad de buen pronóstico que se resuelve antes del año de vida con el aclaramiento de los anticuerpos maternos. El lupus eritematoso neonatal puede presentar manifestaciones cardiacas (50%), cutáneas (50%) o coexistencia de ambas (10%). Su diagnóstico requiere un alto índice de sospecha, incluyendo una buena historia clínica con antecedentes familiares

Cutaneous neonatal lupus is an entity with good prognosis, it is resolved within the first year of age with the clearance of maternal antibodies. Neonatal lupus erythematosus may present cardiac (50%), cutaneous (50%) or coexistence of both (10%). Its diagnosis requires a high index of suspicion, including a good clinical history with a family history