A child who presents with blistering that is not due to an infectious cause can represent a diagnostic challenge for primary care physicians. Pediatric autoimmune bullous diseases encompass several very uncommon blistering skin conditions, including chronic bullous disease of childhood (CBDC), pemphigus vulgaris and pemphigus foliaceus, bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita. The hallmark of these diseases is bullae or blistering caused by autoantibody-mediated disruption of the structural anchoring components of the epidermis that results in microscopic and macroscopic cleavage, either intraepidermal or subepidermal.
We report a case of a child with a classic clinical presentation of CBDC, characterized by the crown-of-jewels or string-of-pearls sign, in which vesicles and bullae form in close proximity with an annular morphology. The presentation may mimic herpes simplex and varicella zoster virus infection. A comprehensive search of MEDLINE, EMBASE, and Scopus databases using the key words CBDC, linear IgA disease, and pediatric autoimmune bullous disease allowed for the collection of English-language articles.
Case
An 11-year-old girl with an unremarkable medical and family history presented to the emergency department with multiple annular blistering plaques on her upper back. There was no mucosal or scalp involvement. She was diligently applying medium-potency topical corticosteroid and 1% mupirocin ointments to the lesions, without benefit. Findings of a systems inquiry were negative. On examination, we observed a polycyclic eruption of annularly arranged vesicles—the classical string-of-pearls pattern—extending across the patient’s upper back (Figure 1). Findings on examination of the rest of her skin, mucous membranes, nails, and hair, as well as her lymph nodes, abdominal viscera, and chest, were unremarkable.
Polycyclic eruption of vesicles in the classical string-of-pearls pattern on the patient’s upper back
Discussion
The approach to differential diagnosis of skin blistering in children varies with the age at presentation. In infancy and in school-aged children, infectious causes are most common; therefore, excluding infections such as herpes simplex and varicella zoster virus, bullous impetigo, and staphylococcal scalded skin syndrome is important. Bacterial and viral swabs are essential for microscopy, culture, and viral polymerase chain reaction. In children, blistering due to arthropod bites (including bullous scabies1) is also common.
Once these common presentations have been excluded, it is important to consider less frequent causes. Rare causes of generalized blistering in children include immune-mediated blistering disorders. These include CBDC, dermatitis herpetiformis, bullous pemphigoid, pemphigus vulgaris and pemphigus foliaceus, and epidermolysis bullosa acquisita. Children might also present with blisters that appear in association with rare variants of cutaneous lupus erythematosus,2 lichen sclerosus,3 and lichen planus (Table 1).4 Chronic bullous disease of childhood is the most common pediatric autoimmune bullous disease. Its pathophysiology is analogous to linear immunoglobulin (Ig) A disease in adults.5 In CBDC, autoantibodies target antigens that are components of the hemidesmosome, a complex molecular structure that is essential for dermal-epidermal junction stability and, therefore, for adherence of the epidermis to the dermis.
Key features and differential diagnoses of CBDC
Onset of CBDC is typically between 6 months and 5 years of age (average 4.5 years6). Rare neonatal cases have been described.7 The incidence of CBDC has not been definitively determined. There is no ethnic predilection, and boys and girls are equally affected. There might be a genetic association with human leukocyte antigen (HLA) haplotypes HLA-B8,6 HLA-Cw7,8 and HLA-DR3.9
With CBDC, the vesicles and bullae are tense, filled with clear or hemorrhagic sera, and 0.3 to 2.0 cm in diameter. Although CBDC is generally thought to be idiopathic, there are several reports suggesting an infectious or drug10,11 provocation, with the antibiotic vancomycin being the most common culprit.
The blistering in CBDC may present anywhere on the body but is particularly problematic if it involves the mucous membranes of the mouth or genitals. The lesions do not scar when healed but may leave behind postinflammatory dyspigmentation. The most concerning potential complication of CBDC is ocular mucosal blistering, which might lead to permanent vision loss or blindness.
Workup. Although clinically the string-of-pearls sign is characteristic, skin biopsy is the criterion standard diagnostic test. A skin biopsy elucidates the level at which the epidermal separation is occurring. A good rule of thumb is that if an intact blister is seen on presentation, the plane of cleavage is dermal (suggesting subepidermal pathology) rather than intraepidermal (seen in staphylococcal scalded skin syndrome, other infectious causes of blistering, and pemphigus).
As CBDC is an autoimmune-mediated disorder, perilesional, clinically normal skin should also be biopsied for direct immunofluorescence studies, a 1-step technique using the patient’s fresh skin. Immunofluorescence studies reveal the pattern of antibody deposition, thereby narrowing the differential diagnosis. The frozen sample is exposed to labeled antihuman IgG, IgA, IgM, complement, and fibrinogen solutions. Under a fluorescence microscope, CBDC is characterized by a striking linear deposition of IgA along the basement membrane (Figure 2).
Fluorescence microscopy of the linear deposition of immunoglobulin A along the basement membrane in chronic bullous disease of childhood
Treatment considerations. Usually, CBDC is self-limiting, and in most cases blistering resolves spontaneously within 2 to 5 years.12 Most children are offered intervention to provide symptomatic relief. Unfortunately, because CBDC is rare, there is little evidence on which to base comparison of treatment options in pediatric cases, which is a considerable knowledge gap; however, successful treatment approaches can be gleaned from retrospective case reports and small case series.
Topical corticosteroids as monotherapy are considered if disease is mild. First-line systemic treatment is dapsone or sulfapyridine, usually maintained for 8 to 12 months.13 Dapsone appears to prevent the binding of IgA and neutrophils to the epidermis, thus preventing local inflammation and resultant blistering.14 There are several retrospective case series reporting that children with CBDC experience rapid improvement using dapsone (0.5 to 2 mg/kg/d) or sulfapyridine (15 to 60 mg/kg/d).5 Marsden et al treated 20 children, successfully inducing remission in 12 (60%) with either dapsone or sulfapyridine alone. The remaining 8 children needed systemic corticosteroids.15 Baseline screening laboratory tests must include measurement of the glucose-6-phosphate dehydrogenase level to avoid hemolytic anemia. Uncommon side effects include dapsone hypersensitivity syndrome and peripheral neuropathy (often motor, with doses of 2 to 3 mg/kg).
Colchicine has been described as a monotherapy for CBDC (0.5 to 0.6 mg, twice daily), especially for patients in whom dapsone is contraindicated.16 Banodkar and al-Suwaid prospectively looked at 8 children with CBDC who were treated with colchicine17 and saw complete remission in 5 of them within 4 to 6 weeks. Side effects include gastrointestinal upset, myelosuppression, and peripheral neuropathy with long-term use.18
Several classes of antibiotics have been used in the treatment of CBDC, including penicillins and macrolides. They are effective owing to their anti-inflammatory rather than antibiotic effect. Classes of antibiotics other than dapsone or sulfapyridine are an attractive alternative, as they require less monitoring and have an acceptable safety record.19
While most children experience a benign self-limited course, complications can be devastating. The mucous membranes may be affected in up to 76% of patients, a process that can be severe and scarring.15 Extensive conjunctival involvement and possible airway compromise20 have both been documented.
Conclusion
The differential diagnoses for skin blistering in infants and children are extensive and include both common and very rare disorders.
If infectious causes have been excluded and autoimmune blistering is suspected, referral to a pediatric dermatologist is recommended, given that skin biopsy in children might entail their conscious sedation under local anesthetic to prevent causing them undue distress, and this requires specific training to perform.
Finally, considerable and devastating mucosal scarring can occur, and there is a low threshold to involve a multidisciplinary team including otolaryngology, ophthalmology, gynecology, or urology early in the patient’s course.21
Acknowledgment
We thank Dr John Mee of the Immunodermatology laboratory at the St John's Institute of Dermatology in London, UK, for permission to use the photograph in Figure 2.
Notes
Editor’s key points
▸ Chronic bullous disease of childhood is the most common pediatric autoimmune bullous disease. It presents with tense blisters, often in the classic string-of-pearls or crown-of-jewels pattern.
▸ The condition is often self-limiting and can resolve spontaneously without treatment. Mild cases can be treated with topical corticosteroids.
▸ Dapsone or sulfapyridine are the first-line systemic treatments, and the patient’s glucose-6-phosphate dehydrogenase level must be measured before starting these medications. Other treatments include colchicine and penicillin or macrolide antibiotics.
▸ The differential diagnoses for skin blistering in infants and children are extensive and include both common and very rare disorders. If infectious causes have been excluded and autoimmune blistering is suspected, referral to a pediatric dermatologist is recommended.
Points de repère du rédacteur
▸ La maladie chronique bulleuse de l’enfance est la plus commune des affections bulleuses auto-immunes pédiatriques. Elle se présente sous la forme de cloques tendues, souvent semblable à un collier de perles ou à des joyaux sur une couronne.
▸ L’affection se résorbe souvent d’elle-même et peut disparaître spontanément sans traitement. Les cas bénins peuvent être traités avec des corticostéroïdes topiques.
▸ La dapsone ou la sulfapyridine sont les traitements systémiques de première intention, mais avant de commencer ces médicaments, il faut d’abord mesurer le taux de la glucose-6-phosphate déshydrogénase chez le patient. Parmi les autres traitements figurent la colchicine et la pénicilline ou des antibiotiques macrolides.
▸ Les diagnostics différentiels pour la formation de cloques cutanées chez les nourrissons et les enfants sont nombreux et incluent à la fois des troubles communs et des troubles très rares. Si des causes infectieuses ont été exclues et si la formation de cloques auto-immunes est suspectée, il est recommandé de demander une consultation en dermatologie pédiatrique.
Footnotes
Competing interests
None declared
This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
- Copyright © 2022 the College of Family Physicians of Canada
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