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Objective Cutaneous disease associated with placental transport of maternal anti-SSA/Ro or anti-SSB/La antibodies is transient, and children often appear to be otherwise healthy. However, the impact of this manifestation of neonatal lupus (NL) on the risk of cardiac disease occurring in a future pregnancy is critical for family counseling and for powering preventive trials. The purpose of this study was to determine the recurrence rates of NL, with specific focus on cardiac NL following cutaneous NL in a child enrolled in the Research Registry for Neonatal Lupus (RRNL). Methods Fifty-eight families who were enrolled in the RRNL met the following inclusion criteria for our study: maternal anti-SSA/Ro or anti-SSB/La antibodies, a child with cutaneous NL, and a pregnancy subsequent to the child with cutaneous NL. Results The majority of the 58 mothers (78%) were Caucasian. Of 77 pregnancies that occurred following the birth of a child with cutaneous NL, the overall recurrence rate for any manifestation of NL was 49% (95% confidence interval [95% CI] 37–62%); 14 pregnancies (18.2%) were complicated by cardiac NL, 23 (29.9%) by cutaneous NL, and 1 (1.3%) by hematologic/hepatic NL. A subset analysis was restricted to the 39 children who were born after the initial child with cutaneous NL had been enrolled in the RRNL. The overall recurrence rate for NL was 36% (95% CI 20–52%); 5 pregnancies (12.8%) were complicated by cardiac NL and 9 (23.1%) by cutaneous NL. There were no significant differences in the following maternal risk factors for having a subsequent child with cardiac or cutaneous NL: age, race/ethnicity, anti-SSB/La status, diagnosis, use of nonfluorinated steroids, or breastfeeding. The sex of the subsequent fetus did not influence the development of cardiac or cutaneous NL. Conclusion Based on data from this large cohort, the identification of cutaneous NL in an anti-SSA/Ro antibody–exposed infant is particularly important, since it predicts a 6–10-fold risk of a subsequent child developing cardiac NL.

Several hereditary and nonhereditary gastrointestinal tract polyposis syndromes exhibit extra-intestinal manifestations, including cutaneous findings. However, a lack of information exists regarding cutaneous features of juvenile polyposis. Our objective was to document the prevalence of cutaneous hyperpigmented lesions in children with juvenile polyposis coli or juvenile polyposis coli and their first degree relatives. Children seen in the gastroenterology practice at The Children's Hospital in Denver, Colorado with polyps (juvenile polyposis coli, sporadic juvenile polyps, and familial adenomatous polyposis coli) and their first degree relatives were invited to participate in the study. A comprehensive skin examination was performed on those who consented to participate. We found that 8 of 14 patients (eight with juvenile polyposis coli, four with juvenile polyposis, and two with familial adenomatous polyposis coli) had at least one cafe-au-lait macule, compared with three of 27 relatives (p = 0.003). The prevalence of at least one cafe-au-lait macule in our patients (8/14 or 57.1%, CI: 28.9–82.3%) was significantly higher than the general population prevalence of 28.5% (p = 0.023). However, if the two patients with familial adenomatous polyposis coli were excluded, the comparison with the general population prevalence did not reach statistical significance (p = 0.095). The prevalence of multiple cafe-au-lait macules in our patients (4/14 or 28.6%; CI: 8.4–58.1%) was significantly higher than the general population prevalence of 5.2% (p = 0.005). A notable finding was the presence of multiple cafe-au-lait macules in 4 of 12 juvenile polyposis coli/juvenile polyposis patients. Two patients with juvenile polyposis coli also had lentigines. In this selected case series, we observed single or multiple cafe-au-lait macules in a high proportion of children with the three types of polyps. Further studies are needed to assess a possible common pathway for hamartomatous polyps and cafe-au-lait macules.

Objective Cutaneous neonatal lupus resembles subacute cutaneous lupus erythematosus (SCLE), and photosensitivity is a common symptom. Tumor necrosis factor α (TNFα) release by ultraviolet light–exposed keratinocytes may be exaggerated in SCLE patients who have the haplotype TNFα −308A;DRB1*03. Accordingly, this study was undertaken to seek genetic and histologic evidence for a role of TNFα in the pathogenesis of cutaneous neonatal lupus. Methods DNA was isolated from 83 children (22 with rash, 35 with congenital heart block [CHB], 26 unaffected siblings) and 58 mothers from the Research Registry for Neonatal Lupus. Results The −308A allele (associated with higher TNFα production), HLA–DRQB1*02, and HLA–DRB1*03 were each present in the majority of children with rash (64%, 68%, and 64%, respectively). The frequency of all 3 6p alleles occurring together in 1 individual was greater in children with rash than in children who had either CHB or no manifestation of neonatal lupus (59% versus 30%; P = 0.02). This association with neonatal lupus rash was equivalent to published findings in a cohort of patients with SCLE, but significantly greater than the association in patients with discoid lupus erythematosus. Prominent TNFα staining in the epidermis was observed in lesional skin from 3 children with rash, but not in skin from a healthy neonate. Conclusion Taken together, the finding of a genetic predisposition to generate increased levels of TNFα following tissue injury and the histologic demonstration of TNFα in the target organ support the notion that this inflammatory cytokine plays a role in the pathogenesis of cutaneous neonatal lupus. Furthermore, the results of these studies provide evidence of a biologic link between neonatal lupus and the rash of SCLE.

Objective To determine in a longitudinal cohort study whether children with varied manifestations of neonatal lupus or their unaffected siblings later develop autoantibodies and/or rheumatic diseases. Methods To obtain information on the health of children ages ≥8 years who had manifestations of neonatal lupus (affected group) and their unaffected siblings (unaffected group), questionnaires were sent to mothers (with anti-SSA/Ro and/or anti-SSB/La antibodies) who were enrolled in the National Institute of Arthritis and Musculoskeletal and Skin Diseases/Hospital for Joint Diseases Research Registry for Neonatal Lupus. Children of healthy mothers referred by the Registry enrollees comprised the control group. Further data were provided by review of medical records. Results Fifty-five mothers enrolled in the Registry returned questionnaires on 49 children with neonatal lupus and their 45 unaffected siblings. Six children with definite rheumatic/autoimmune diseases were identified: 2 with juvenile rheumatoid arthritis, 1 with Hashimoto thyroiditis, 1 with psoriasis and iritis, 1 with diabetes mellitus and psoriasis, and 1 with congenital hypothyroidism and nephrotic syndrome. All had neonatal lupus, and their mothers had manifestations of autoimmune diseases (Sjogren's syndrome in 4, systemic lupus erythematosus/Sjogren's syndrome in 1, and undifferentiated autoimmune disease in 1). Antinuclear antibodies were present in 4 of 55 sera tested (2 of 33 affected children and 2 of 22 unaffected children). No serum contained antibodies reactive with SSA/Ro or SSB/La antigens. Conclusion These data suggest that children with neonatal lupus require continued followup, especially prior to adolescence and if the mother herself has an autoimmune disease. While there was no apparent increased risk of systemic lupus erythematosus, the development of some form of autoimmune disease (systemic or organ-specific) in early childhood may be of concern. During adolescence and young adulthood, individuals with neonatal lupus and their unaffected siblings do not appear to have an increased risk of developing systemic rheumatic diseases.

Chronic ulcerative stomatitis protein (CUSP), the most abundant cutaneous isoform of p63, is a p53-related gene essential for epithelial development. CUSP lacks the N-terminal transactivation domain found on other p53 family members and has been shown to inhibit p53 function in vitro. In this study, biopsies of normal skin (21 of 21), benign neoplasms [seborrheic keratosis (3 of 3), acrochordon (2 of 3), and verruca plana (3 of 3)], and squamous cell carcinomas (SCC) (4 of 4) displayed strong nuclear CUSP immuno-reactivity in epidermal cells. In contrast few basal cell carcinomas (BCC) (7 of 27) and sebaceous nevi (1 of 2) displayed this pattern of CUSP immunoreactivity. Thus, biopsies of cutaneous conditions characterized by sonic hedgehog (SHH) pathway dysregulation were more than 86 times as likely to lack CUSP/p63 immunofluorescence as were other cutaneous samples. Adjacent normal-appearing skin from patients with basal cell nevus syndrome (BCNS) (2 of 3) also lacked CUSP immuno-staining. Lastly, a BCC arising in a patched heterozygous mouse also lacked CUSP immuno-staining. Because CUSP mRNA and protein were detected via Northern and Western analysis in BCC samples lacking CUSP immuno-staining, we sequenced the coding region of CUSP from two non-staining BCCs but found no mutations. Therefore, CUSP appears to be present, unmutated, and yet frequently undetectable by immunofluorescence in cutaneous lesions in both humans and mice that are associated with SHH pathway dysregulation (BCCs, BCNS, and nevus sebaceous).