Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block.

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.

Lipodystrophy and metabolic abnormalities in a case of adult dermatomyositis.

Lipodystrophy and metabolic abnormalities, primarily hypertriglyceridemia and insulin resistance, have been reported in juvenile dermatomyositis. We report a 55-year-old woman with adult dermatomyositis who developed lipodystrophy of the thighs, hypertriglyceridemia, and insulin resistance. Our case illustrates that lipodystrophy may occur in adult and juvenile dermatomyositis. Loss of subcutaneous tissue may be a cutaneous marker for metabolic abnormalities in both the adult and the juvenile forms of dermatomyositis.

deltaNp63alpha functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes.

deltaNp63 is overexpressed in squamous carcinomas where it is associated with proliferation and is believed to enhance cell growth by blocking p53-mediated transactivation. In normal epithelium, deltaNp63alpha protein expression is abundant in basal cells and decreases with differentiation. To explore the biological consequences of deltaNp63alpha overexpression in relation to squamous carcinogenesis, we evaluated its effect on normal squamous differentiation and p53 transactivation function in keratinocytes. Forced overexpression of deltaNp63alpha in primary murine keratinocytes in vitro inhibits morphological differentiation induced by elevated extracellular [Ca(2+)], abrogates Ca(2)(+)-induced growth arrest, and blocks expression of maturation-specific proteins keratin 10 and filaggrin. This suggests that deltaNp63 overexpression in squamous carcinomas may serve to maintain the basal cell phenotype and promote cell survival. deltaNp63alpha blocks transactivation of p53 responsive reporter constructs mediated by endogenous or exogenous p53 at 17 h postinfection, as expected. However, at 41 h, when p53-mediated transactivation is diminished, deltaNp63alpha enhances transactivation of these reporter constructs by 2.2-12-fold over control. Maximal deltaNp63alpha-induced transactivation requires intact p53 responsive elements, but is independent of cellular p53 status. This positive transcriptional function of deltaNp63alpha appears to be cell-type specific, as it is not observed in primary dermal fibroblasts or Saos-2 cells. These findings support deltaNp63alpha as a master regulator of keratinocyte differentiation, and suggest a novel function of this protein in the maintenance of epithelial homeostasis.

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.

The CUSP DeltaNp63alpha isoform of human p63 is downregulated by solar-simulated ultraviolet radiation.

BACKGROUND: In normal human keratinocytes, a p53-like protein, DeltaNp63alpha, also known as CUSP, is constitutively and abundantly expressed. The significant constitutive expression of DeltaNp63alpha in stratified epithelium has been proposed to maintain the proliferative capacity of basal cells, blocking the consequences of inappropriate p53 activation. OBJECTIVE: To determine the response of keratinocyte DeltaNp63alpha to ultraviolet radiation (UVR), a stimulus for p53 activation. METHODS: Cultured normal human keratinocytes were exposed to graded doses of solar-simulated UVR. The expression of DeltaNp63alpha protein and mRNA were measured with Western and Northern blotting. Normal mouse skin was exposed to UVR, and DeltaNp63alpha expression assessed with immunohistochemistry. RESULTS: Increasing doses of UVR virtually shut off DeltaNp63alpha protein and mRNA expression in cultured normal human keratinocytes and in normal mouse skin in vivo. CONCLUSION: This study supports the hypothesis that in situations where p53 activation is desirable, as with DNA-damaging UVR, DeltaNp63alpha downregulation occurs and may possibly allow for better target gene transcription by p53.

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.

Neonatal lupus erythematosus.

Neonatal lupus erythematosus is associated with cutaneous lesions, CHB, hepatic disease, and thrombocytopenia. IgG antibodies to Ro and/or La cross the placenta and participate in the development of the clinical manifestations. Mothers of babies with NLE are likely to develop collagen vascular diseases with time. Infants with NLE are at risk to develop other autoimmune diseases during childhood or adolescence.

Evaluation of reliability, validity, and responsiveness of the CDASI and the CAT-BM.

To properly evaluate therapies for cutaneous dermatomyositis (DM), it is essential to administer an outcome instrument that is reliable, valid, and responsive to clinical change, particularly when measuring disease activity. The purpose of this study was to compare two skin severity DM outcome measures, the Cutaneous Disease and Activity Severity Index (CDASI) and the Cutaneous Assessment Tool-Binary Method (CAT-BM), with the Physician Global Assessment (PGA) as the "gold standard". Ten dermatologists evaluated 14 patients with DM using the CDASI, CAT-BM, and PGA scales. Inter- and intra-rater reliability, validity, responsiveness, and completion time were compared for each outcome instrument. Responsiveness was assessed from a different study population, where one physician evaluated 35 patients with 110 visits. The CDASI was found to have a higher inter- and intra-rater reliability. Regarding construct validity, both the CDASI and the CAT-BM were significant predictors of the PGA scales. The CDASI had the best responsiveness among the three outcome instruments examined. The CDASI had a statistically longer completion time than the CAT-BM by about 1.5 minutes. The small patient population may limit the external validity of the findings observed. The CDASI is a better clinical tool to assess skin severity in DM.

The clinical spectrum of neonatal lupus.

Neonatal lupus is an uncommon condition associated with maternal anti-Ro autoantibodies. Findings may include cutaneous lupus lesions, third-degree heart block, cardiomyopathy, hepatobiliary disease, and/or thrombocytopenia or other hematologic cytopenias. It is common for only one organ to be affected, but any combination of organ involvement may occur. Recent studies have raised the possibility that the central nervous system may also be affected, but if it is, it is generally apparently asymptomatic. The most common severe manifestation of neonatal lupus is third-degree heart block, which usually begins during the second trimester of gestation. Attempts have been made to prevent the development of heart block, most often by treating the mother with systemic corticosteroids during pregnancy. There is not yet consensus as to the value of intervention during pregnancy. The neonatal lupus disease process is transient, although third-degree heart block, once established, is permanent. Cutaneous lesions tend to resolve completely and affected individuals tend to be healthy later in childhood. There does appear to be an increased risk for children who have had neonatal lupus to develop autoimmune diseases later in childhood or adulthood. The magnitude of that risk is uncertain. Mothers, who are often asymptomatic at the time of delivery of a baby with neonatal lupus, tend eventually to develop signs and symptoms of autoimmune disease.

Tattoo pigment interpreted as lymph node metastasis in a case of subungual melanoma.

We present a patient with subungual melanoma of the thumb who, during radioisotope-guided selective sentinel lymphadenectomy, was found to have black, hard lymph nodes at multiple axillary node levels. This finding was interpreted intraoperatively as clinical evidence of metastasis and a formal axillary dissection was carried out. Pathological examination of excised nodes failed to demonstrate metastasis but instead showed collections of tattoo pigment.

Café au lait macules and juvénile polyps.

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 café-au-lait macule, compared with three of 27 relatives (p=0.003).The prevalence of at least one café-au-lait macule in our patients (8/14 or 57.1%, CI: 28.9­82.3%) 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:8.4­58.1%) was significantly higher than the general population prevalence of 5.2% (p » 0.005). A notable finding was the presence of multiple café -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 café-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 polypsand café-au-lait macules.

Neonatal lupus erythematosus: clinical findings and pathogenesis.

Neonatal lupus erythematosus is an uncommon disease associated with maternal autoantibodies to proteins of the Ro/La (SSA/SSB) family. The clinical findings most often reported are third-degree heart block and cutaneous lupus lesions, but a significant number of children have cardiomyopathy, hepatobiliary disease, or hematologic cytopenias. The consistent presence of maternal autoantibodies and the transient nature of the disease implicate maternal autoantibodies as the cause of the disease, and developing animal models support the concept that the autoantibodies are pathogenic. Only a minority of babies exposed to the autoantibodies develop disease, however, and mothers and their babies have different disease manifestations. Thus, additional factors are likely to be important in determining disease expression.

Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry.

OBJECTIVE: To extend the information base on the hepatobiliary manifestations of neonatal lupus erythematosus (NLE) with regard to frequency of occurrence, clinical characteristics, and outcome. METHODS: Review of records from the Research Registry for Neonatal Lupus. RESULTS: Nineteen (9%) of 219 patients who had NLE and were enrolled in a national registry had probable or possible NLE hepatobiliary disease. In 16 cases, hepatobiliary disease occurred in addition to cardiac or cutaneous NLE. In 3 cases, hepatobiliary disease occurred as the sole clinical manifestation of NLE. Three clinical variants of hepatobiliary disease were observed: 1) severe liver failure present during gestation or in the neonatal period, often with the phenotype of neonatal iron storage disease; 2) conjugated hyperbilirubinemia with mild or no elevations of aminotransferases, occurring in the first few weeks of life; and 3) mild elevations of aminotransferases occurring at approximately 2 to 3 months of life. The prognosis for the children in the last 2 categories is excellent. CONCLUSIONS: Hepatobiliary disease is a relatively common finding in NLE and can be the sole clinical manifestation of NLE. Clinicians should be aware of the broad range of hepatobiliary disease that may occur in children with NLE.