Neonatal Linear Immunoglobulin A Bullous Dermatosis: A Critical Case Recovering after Prompt Recognition, Intensive Management, and Breastfeeding Interruption – A Case Report

Linear immunoglobulin A (IgA) bullous dermatosis is a blistering disease that affects both children and adults, with rare onset during the neonatal period; so far less than 20 cases of neonatal linear IgA bullous dermatosis (NLABD) have been reported [1]. NLABD manifests in the first days of life with cutaneous vesicles and bullae, organized in a circular “string of pearls” pattern, combined with erosions and crusted lesions. Mucosal involvement of the upper aerodigestive tract is the most serious complication, which leads to feeding difficulties and life-threatening respiratory failure. Respiratory support and tube feeding are indicated in most cases. Ophthalmologic manifestations are occasionally reported [2]. The mechanism of IgA transmission is not fully elucidated yet, but the presence of auto-IgAs in breastmilk suggested that mother’s milk could be the main transmission source [3].

A full-term female newborn, second child of healthy parents, was born by spontaneous vaginal delivery. The pregnancy and mother’s routine serologies were unremarkable. She was exclusively breastfed and discharged home on the third day of life (DOL).

On DOL 6, multiple blisters appeared on genitalia and periumbilical area, forearms, and legs. She was examined at the paediatric emergency. Assuming a benign transient neonatal pustular melanosis, she was discharged home without further investigations nor treatment. On DOL10, parents noticed progressive worsening of her skin lesions, alteration of her general condition, and alertness. She was hospitalized and received acyclovir. The treatment was discontinued 24 h later, secondary to the negative results of a broad PCR and culture panel for herpes and other viral and bacterial infections.

A skin biopsy was performed on DOL 11, and she was kept under clinical observation. By DOL 13, she presented feeding difficulties and developed a stridor associated with severe respiratory deterioration. The patient was transferred to the neonatal intensive care unit, and non-invasive ventilation (BiPAP) was started. Physical examination at admission revealed erosions in the oral cavity, and extensive skin blisters (Fig. 1). Facing this association of skin and oral lesions, and subsequent respiratory failure, the dermatologist consultants suspected an NLABD and we therefore initiated hydrocortisone (4 mg/kg/day) and discontinued breastfeeding. The day after, the biopsy confirmed this diagnosis: histology showed subepidermal vesicles containing numerous neutrophils, and direct immunofluorescence revealed pathognomonic linear IgA and C3 deposition along the basement membrane zone (Fig. 2) excluding IgA pemphigus. Indirect immunofluorescence with the mother’s milk using salt-split skin revealed presence of IgAs attacking the basement membrane of skin and mucosa (anti-BMZ IgAs) while these antibodies were not found in mother’s nor patient’s serum.

The investigations were completed by laryngo-tracheoscopy and oesophago-gastroscopy, proving oedema and erosions of the epiglottic, supraglottic, subglottic, and gastric mucosa (Fig. 1). Ophthalmological examination ruled out keratitis.

She was kept under intensive care, with non-invasive ventilation, enteral nutritional support by formula gastric tube feeding, wound care, and slowly tapered systemic corticoid treatment. By DOL 55, all skin blisters healed. On DOL 57, BiPAP and corticosteroid were discontinued. The patient recovered completely and gained full oral feeding. Formula feeding was maintained. She was discharged home on DOL 64. The follow-up at 4 and 15 months revealed no signs of relapse.

NLABD is characterized by anti-BMZ IgAs. However, in neonates, this raises several questions, as the neonatal immune system is immature and unlikely to cause such an auto-immune IgA-mediated disorder [4]. By contrast to IgG autoantibody cases, mothers of infants with NLABD are usually asymptomatic, and no autoantibodies are detected in their serum. To our knowledge, our report is among the first to identify and document anti-BMZ IgAs in a mother’s breastmilk, confirming the findings of Egami et al. [3].

One might draw several hypotheses for maternal pathogenic IgAs in breastmilk, despite the mother’s lack of symptoms and absence of anti-BMZ IgAs in their serum [3]. First, a mother’s intestinal microflora before and after birth might affect secretory IgA level in breastmilk [4]. Second, stimulated by the hormonal changes occurring during the third trimester of pregnancy, memory B cells migrate towards the mammary gland where they produce high amounts of IgAs that pass the mammary gland barrier to be found in colostrum and mother’s milk [5].

Maternal IgA transfer to the systemic circulation of infants is usually believed to be negligible [5]. However, it could possibly occur in the first 48 h of life, due to a higher digestive mucosa permeability. Both literature and our case indicate that cutaneous involvement appears before respiratory or digestive symptoms. This implies subclinical mucosal damages from direct IgA contact that might allow systemic IgA passage to the skin, where the target basement antigen is most highly expressed.

In these conditions, NLABD must be suspected based on the typical cutaneous lesions followed by upper digestive and respiratory mucosa involvement, in a healthy neonate. However, other conditions must be ruled out, as we did in our case, including infectious, immunological disorders, as well as other dermatological diseases such as, among others, epidermolysis bullosa, and various autoimmune bullous diseases, including neonatal lupus.

Therefore, a prompt skin biopsy is crucial to reveal typical subepidermal blistering and dermal inflammation. Direct immunofluorescence allows identification of pathogenic IgAs deposited along the dermo-epidermal junction, as well as immunoreactants such as C3 [6, 7].

There is currently no consensus on optimal management of NALBD. However, discontinuation of breastfeeding is recommended, despite acknowledged benefits of breastmilk. Dapsone is classically proposed in first-line treatment for LABD. However, in the neonatal period, hydrocortisone needs to be considered to avoid dapsone’s potential concerning side effects.

Treatment duration should be adapted based on clinical response, with progressive tapering. Besides appropriate respiratory support, feeding requires special attention, additionally to local wound care. Most cases reported in the literature had severe respiratory and gastrointestinal tract sequelae, which fortunately could be avoided in this patient.

NLABD is a rare life-threatening disease raising several diagnostic and management challenges. Multidisciplinary collaboration is a crucial factor for a prompt diagnosis and adequate management, which appear fundamental for determining a disease’s prognosis. In case of suspected or confirmed NLABD, we advise discontinuing breastfeeding, introducing systemic corticoids, and immediately transferring patients into NICU.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent for publication of case: written informed consent was obtained from the parents of the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

This case report was not supported by any sponsor or funder.

D.P. and S.J. identified the case. D.P. wrote the manuscript with support from S.J., C.J.F.F., M.M., and E.G. L.D., L.F., L.B., F.G., and T.F. critically revised the manuscript for important intellectual content. All the authors accepted the final version of the manuscript.

The data that support our findings are not publicly available due to the risk of compromising the identity of our patient. However, anonymized data can be made available from the corresponding author S.J. upon reasonable request.