Neonatal lupus erythematosus (NLE), first described by Bridge and Foley in 1954, is an autoimmune syndrome caused by the transplacental transmission of maternal autoantibodies, primarily anti-SSA/Ro and anti-SSB/La, and occasionally anti-U1RNP, which bind to fetal tissues (1–3). The incidence of NLE is approximately 1 in 12,500–20,000 live births, with a 2% occurrence in children of mothers carrying these antibodies and an 18%–20% recurrence risk in subsequent pregnancies (3, 4).

Clinically, NLE presents with various manifestations, including the characteristic periorbital annular skin rash (often referred to as an “eye mask” or “raccoon-like” appearance), cytopenia, hepatitis, and, most severely, congenital heart block (CHB) (3, 5).

In NLE, autoantibodies are prevalent in both children and their mothers. Children commonly test positive for anti-SSA (87.5%), anti-SSB (50%), or both (55%), and occasionally for anti-U1RNP (6, 7), while mothers exhibit similar rates: 84.6% for anti-SSA, 58.9% for anti-SSB, and 35.5% for both (8). Additionally, mothers may exhibit other autoantibodies depending on their underlying autoimmune diseases, such as systemic lupus erythematosus (SLE) or Sjögren's syndrome (3, 6).

Diagnosis relies on clinical presentation and detection of anti-SSA/Ro and/or anti-SSB/La in both the infant and mother; skin biopsy is optional (9). Differential diagnoses include congenital syphilis, tinea corporis, sarcoidosis, granuloma annulare, Langerhans histiocytosis, Sweet syndrome, and urticaria (3).

A significant proportion (25%–60%) of mothers are asymptomatic, which poses diagnostic challenges and increases the risk for their offspring (5, 10). Infants may develop other autoimmune diseases later, highlighting the importance of screening women of reproductive age for autoantibodies, even those with mild symptoms (5, 11, 12).

While the global incidence of NLE is a concern, the true incidence is likely underestimated (4). In China, the combination of a large population exceeding 1.4 billion (13) and a high prevalence of autoimmune diseases, such as Sjögren's syndrome (0.33%–0.77%) (14) and SLE (14.09 per 100,000 person-years in 2017) (15), suggests a considerable potential impact of NLE in the country. Furthermore, the implementation of the two-child policy in 2016 may lead to an increase in the incidence of CHB in NLE infants and a rise in overall NLE cases among siblings due to higher numbers of second births (12, 16). These factors collectively highlight the significant public health implications of NLE in China.

Management includes serial fetal echocardiograms biweekly between 16 and 28 weeks' gestation (3, 5), sun protection for cutaneous manifestations (5), and hydroxychloroquine to potentially reduce the recurrence of CHB (17). The role of intravenous immunoglobulin (IVIG) is under investigation (18). The prognosis of NLE varies. Cutaneous, hematologic, and hepatic abnormalities are typically transient. However, CHB can be potentially permanent, particularly third-degree CHB, which is more severe and frequently requires pacemaker implantation due to its significant mortality (20%–30%) and morbidity (19, 20).

These factors underscore the critical need for further research and enhanced surveillance, particularly in countries like China, to better understand and mitigate the impact of NLE.

The main results of this study highlight the phenotypic diversity of NLE, as evidenced by the varied dermatological manifestations in siblings, including typical annular plaques and atypical red papules. The study's strengths lie in its comprehensive clinical documentation and extended follow-up, providing valuable insights into the natural history and treatment approaches for NLE in sibling pairs. These findings underscore the critical importance of early diagnosis and treatment.

Comparison with the literature reveals that cases of NLE among siblings have been reported, highlighting the variable clinical presentations of NLE within families. This emphasizes the importance of monitoring and preventive measures for mothers with a history of autoimmune diseases and their offspring. Zuppa et al. (23) discuss the differing manifestations of NLE among siblings, while Lee et al. (24) focus on the increased risk of NLE in successive pregnancies for mothers who have previously given birth to a child with NLE. Collectively, these studies underscore the need for vigilant prenatal care and counseling for families with a history of NLE.

The morphology of the NLE rash was heterogeneous, with typical cutaneous lesions resembling those seen in subacute cutaneous lupus erythematosus (SCLE) (3). A retrospective cohort study (25) revealed that annular (70.7%) and papulosquamous (70.7%) rashes were common, while pink/red macules were less frequent (11.1%).

Our findings align with the literature. Case 1 showed typical annular scaly erythema similar to SCLE, while Case 2 had less common red papules and macules, potentially due to varying specificity of anti-Ro autoantibodies or other fetal-maternal factors, including environmental, intrauterine, or genetic influences (23, 26).

The association between maternal treatment adherence and NLE recurrence requires further empirical evidence. However, it is well-recognized that pregnant women testing positive for autoantibodies to SSA/Ro or SSB/La, particularly those with a prior history of NLE, are at increased risk of delivering a child with NLE (4, 6). Furthermore, recent research has highlighted the notable possibility that normal sinus rhythm can progress to third-degree heart block within just 7 days (19). Given these risks, it is essential to monitor the fetal PR interval through echocardiogram during gestation. The absence of such monitoring is deemed potentially hazardous, underscoring the necessity for comprehensive counseling, fetal and maternal screening, and the implementation of preventive or management strategies for heart disease (6, 27). Our findings align with these observations, suggesting that suboptimal adherence to treatment, which may lead to sustained high levels of autoantibodies such as SSA, SSB, and ANA, could contribute to the recurrence of NLE in subsequent pregnancies. This underscores the crucial importance of strict adherence to treatment protocols to minimize recurrence risk and enhance patient outcomes (19).

Preventing NLE in siblings is challenging due to its genetic and autoimmune etiologies. Key prevention strategies include maternal education on autoimmune disease risks and genetic counseling. In our case, the mother, who had experienced xerostomia for over 2 years, only sought medical attention after her first child was diagnosed with NLE. Despite being diagnosed with Sjögren's syndrome and prescribed treatments, her suboptimal adherence to medication may have contributed to the recurrence of NLE in her second child. This underscores the importance of educating mothers about autoimmune disease risks during pregnancy and the necessity of regular prenatal care and autoantibody monitoring (23, 26). Genetic counseling is recommended for families with a history of NLE to discuss the implications of maternal autoimmune diseases and the associated recurrence risks (26). These measures are crucial for informing clinical practice and research, thereby improving outcomes for families affected by NLE (23).

The study is limited by its small sample size, which may restrict the generalizability of the findings. Additionally, the reliance on parental adherence to treatment introduces variability in disease outcomes, as evidenced by the differing levels of maternal treatment adherence in our two cases. Future studies with larger cohorts and standardized treatment protocols are necessary to address these limitations and provide more robust data on NLE management and outcomes (8).

A retrospective cohort study (25) reported cutaneous sequelae in 34% of 106 patients at a mean follow-up duration of 4 years (range 0.5–18.7 years), including 13% telangiectasia, 17% dyspigmentation, and 9% atrophic scarring. Our findings are consistent with these observations: Case 1 exhibited telangiectasia and hyperpigmentation following rash regression, while Case 2 showed no sequelae. The variability in follow-up durations underscores the importance of long-term monitoring to better understand the disease's natural history and long-term outcomes (27).

These sibling cases of NLE with distinct cutaneous manifestations highlight the heterogeneous nature of the disease and underscore the importance of early diagnosis and management. Maternal treatment adherence is crucial for preventing recurrence. Long-term follow-up, including cardiac monitoring, is essential even in the absence of initial cardiac manifestations. These findings emphasize the need for increased awareness among healthcare professionals and expectant mothers about NLE, its potential complications, and the importance of preventive strategies. Further research is needed to explore the underlying mechanisms of NLE and to develop more effective prevention and treatment strategies.